JP2022046588A - Therapeutic compositions and uses thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition for treating or preventing epithelial cancer.

SOLUTION: A pharmaceutical composition comprises, for example, a) 3,8-dihydroxy eicosanoic acid, b) 1-(3,8-dihydroxy eicosanoyl) glycerol, c) 1-(3,8-dihydroxy eicosanoyl) 2-acetoxy g lycerol, d) 1-(3,8-dihydroxy eicosanoyl) 3-acetoxy glycerol, e) 1-(3,8-dihydroxy eicosanoyl) 2,3-diacetoxy glycerol or the like. The compound can be obtained from an extract or exudate of poplar or propolis.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

INDUSTRIAL APPLICABILITY The present invention relates to compositions used in the care of the skin and gastrointestinal tract and in the treatment and prevention of epithelial cancers (eg skin cancer and gastrointestinal cancer). Specifically, the present invention relates to an anti-epithelial cancer composition containing one or more glycerides including dihydroxy fatty acids. Specifically intended are skin and gastrointestinal care, anti-epithelial carcinoma compositions containing one or more dihydroxy fatty acid compounds, and skin disorders, gastrointestinal disorders of such compositions. In the treatment or prevention of mucosal surface disorders and epithelial cancers (eg gastrointestinal cancers such as colonic rectal cancer, throat cancer, cheek cancer and gastric cancer) and skin cancers (eg basal cell carcinoma, squamous epithelial cell carcinoma and melanoma). With use.

Background of the Invention Epithelial cancers include some of the most prevalent cancers in the world. Colorectal cancer has been reported to be the second and third most common cancers in women and men in developed countries, respectively. Colorectal cancer is more prevalent in developed countries (highest in the United States, Australia, Europe and New Zealand) and has a 10-fold higher incidence than in developing countries. Surgery can be effective, but early detection is essential for good surgical outcomes. Other treatments are largely directed to life-prolonging and palliative care, as the effectiveness of current chemotherapy and radiation therapy in the treatment of primary tumors or in the treatment of extralymph node metastases has been debated. ing.

Pharyngeal cancer (also referred to as esophageal cancer, pharyngeal cancer or laryngeal cancer) includes tumors that develop in the tissues of the pharynx, nasopharynx, mesopharynx, hypopharynx, laryngeal (voice) or tonsils. Treatment of throat cancer includes surgery, radiation therapy or chemotherapy. Treatment of laryngeal cancer can hurt the throat and can change the way a patient eats, breathes and sleeps. Existing treatments for cheek cancer have similar problems.

Gastric or stomach cancer is the second most common cause of cancer-related deaths worldwide. Diagnosis is often delayed because symptoms may not appear in the early stages of the disease. The only procedure that can cure gastric cancer is surgery to remove the stomach (gastrectomy). Postoperative chemotherapy and radiation therapy may improve the chances of cure.

Skin cancer is also very prevalent, with more than 3 million cases diagnosed each year in the United States alone. The rate of skin cancer is particularly high in Australia and New Zealand, with an incidence four times higher than in the United States. Surgery can be effective, but early detection is essential for good surgical outcomes. Other treatments are significant as the effectiveness of current chemotherapy and radiation therapy in the treatment of primary tumors (specifically malignant melanoma) or in the treatment of extralymph node metastases has been debated. The part is directed to low-risk diseases.

Thus, anti-epithelial cancer compositions such as those suitable for use in the treatment and prevention of skin cancer and / or gastrointestinal cancer and those that can assist in maintaining or enhance anti-epithelial cancer activity. is needed.

An object of the present invention is in the treatment or prevention of epithelial cancers such as skin cancers such as basal cell carcinomas, squamous cell carcinomas and melanomas and / or gastrointestinal cancers such as colonic rectal cancers, throat cancers, cheek cancers and gastric cancers. To provide an anti-epithelial carcinoma composition for use, or at least to provide a useful option to the public.

（式（Ｉ）中、
Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５はそれぞれ独立してＨまたはアセチル（ＣＨ_３ＣＯ－）であり、
Ｒ_６はＨまたはＣＨ_３であり、Ｒ_７はＣＨ_３またはＣ２～Ｃ６の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して３～１４の整数であり、
但し、Ｒ_６がＨである場合にはｘ＋ｙは１０超且つ１８以下であり、Ｒ_６がＣＨ_３である場合にはｘ＋ｙは９超且つ１７以下である）
の化合物またはその薬学的に許容される塩もしくは溶媒和物の有効な量を投与することを含む方法に関する。一態様では、本発明は、対象の上皮癌を処置するまたは予防する方法であって、必要とする対象に、
ａ）３，８－ジヒドロキシエイコサン酸、
ｂ）１－（３，８－ジヒドロキシエイコサノイル）グリセロール、
ｃ）１－（３，８－ジヒドロキシエイコサノイル）２－アセトキシグリセロール、
ｄ）１－（３，８－ジヒドロキシエイコサノイル）３－アセトキシグリセロール、
ｅ）１－（３，８－ジヒドロキシエイコサノイル）２，３－ジアセトキシグリセロール、
ｆ）１－（３，８－ジアセトキシエイコサノイル）２，３－ジアセトキシグリセロール、
ｇ）３，８－ジヒドロキシエイコサン酸メチルエステル、
ｈ）３，８－ジヒドロキシヘンエイコサン酸、
ｉ）１－（３，８－ジヒドロキシヘンエイコサノイル）グリセロール、
ｊ）１－（３，８－ジヒドロキシヘンエイコサノイル）２－アセトキシグリセロール、
ｋ）１－（３，８－ジヒドロキシヘンエイコサノイル）３－アセトキシグリセロール、
ｌ）１－（３，８－ジヒドロキシヘンエイコサノイル）２，３－ジアセトキシグリセロール、
ｍ）１－（３，８－ジアセトキシヘンエイコサノイル）２，３－ジアセトキシグリセロール、
ｎ）３，８－ジヒドロキシヘンエイコサン酸メチルエステル、
ｏ）３，８－ジヒドロキシドコサン酸、
ｐ）１－（３，８－ジヒドロキシドコサノイル）グリセロール、
ｑ）１－（３，８－ジヒドロキシドコサノイル）２－アセトキシグリセロール、
ｒ）１－（３，８－ジヒドロキシドコサノイル）３－アセトキシグリセロール、
ｓ）１－（３，８－ジヒドロキシドコサノイル）２，３－ジアセトキシグリセロール、
ｔ）１－（３，８－ジアセトキシドコサノイル）２，３－ジアセトキシグリセロール
および
ｕ）３，８－ジヒドロキシドコサン酸メチルエステル
または
ａ）～ｕ）のいずれか１つの薬学的に許容される塩もしくは溶媒和物
からなる群のいずれか１つまたは複数から選択される化合物の有効な量を投与することを含む方法に関する。 Therefore, in the first aspect, the present invention is a method of treating or preventing epithelial cancer of a subject, and the subject in need is formulated (I) :.

(In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less).
The present invention relates to a method comprising administering an effective amount of a compound of the above or a pharmaceutically acceptable salt or solvate thereof. In one aspect, the invention is a method of treating or preventing a subject's epithelial cancer, the subject in need.
a) 3,8-Dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administering an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, the method requires the subject to include at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or a) 3,8-dihydroxyeicosanoic acid.
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable Includes administration of a composition comprising or consisting essentially of, comprising an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, the invention is a method of treating or preventing a subject's skin cancer, wherein the subject in need is at least one compound of formula (I) or a pharmaceutically acceptable salt or solvent thereof. Japanese or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administering an effective amount of a composition comprising or consisting essentially of, comprising a compound selected from any one or more of the group consisting of salts or solvates.

In another aspect, the invention is a method of inhibiting epithelial tumor formation, inhibiting epithelial tumor growth or inhibiting epithelial tumor metastasis of a subject, wherein the compound of formula (I) or to the subject in need. The pharmaceutically acceptable salt or solvate or a) 3,8-dihydroxyeikosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administration of an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, the invention is a method of inhibiting skin tumor formation, inhibiting skin tumor growth or inhibiting skin tumor metastasis of a subject, wherein the compound of formula (I) or a compound thereof to a subject in need. A pharmaceutically acceptable salt or solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administration of an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

Another aspect is a method of inducing apoptosis of one or more neoplastic epithelial cells of a subject in need of a compound of formula (I) or a pharmaceutically acceptable salt thereof or the like. A therapeutically effective amount of solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administration of an effective amount of a composition comprising a therapeutically effective amount of at least one compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, the method is a method of inducing apoptosis of one or more neoplastic skin cells of a subject, wherein the compound of formula (I) or pharmaceutically acceptable thereof to the subject in need. Salt or solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable A method comprising administration of an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, this apoptosis is for basal cancer cells. In another aspect, this apoptosis is for squamous cell carcinoma cells. In a further aspect, this apoptosis is for melanoma cells.

In another aspect, this method is a method of inducing apoptosis of one or more neoplastic gastrointestinal cancer cells of interest.

For example, this apoptosis is for colorectal cancer cells, throat cancer cells, cheek cancer cells or gastric cancer cells.

Another aspect is a method of regulating the growth of one or more neoplastic epithelial cells of a subject, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or to the subject in need. Solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising administration of an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

In one aspect, the invention relates to a method of regulating the growth of one or more neoplastic skin cells of interest.

For example, in one aspect, this regulation is reduced. Accordingly, the present invention is a method of reducing the proliferation of one or more neoplastic skin cells of a subject, wherein the 3,8-dihydroxyeicosanoic acid, 1- (3,8) to the subject in need. -Dihydroxyeicosanoyl) glycerol, 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol, 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxy) Eikosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol, 3,8-dihydroxyeicosanoic acid methyl ester, 3,8-dihydroxyhen Eicosanoic acid, 1- (3,8-dihydroxyheneicosanoyl) glycerol, 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol, 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol, 3, 8-Dihydroxyheneicosanoic acid methyl ester, 3,8-dihydroxydocosanoic acid, 1- (3,8-dihydroxydocosanoyl) glycerol, 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol, 1- (3,8-Dihydroxydocosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxydokosanoyl) 2,3-di The present invention relates to a method comprising administration of an effective amount of a compound selected from the group consisting of acetoxyglycerol and 3,8-dihydroxydocosanoic acid methyl ester.

In one aspect, this proliferation is for basal cancer cells. In another aspect, this proliferation is for squamous cell carcinoma cells. In a further aspect, this proliferation is for melanoma cells.

In one aspect, this method is a method of regulating the growth of one or more neoplastic gastrointestinal cancer cells of interest. For example, this proliferation is for colorectal cancer cells, throat cancer cells, cheek cancer cells or gastric cancer cells.

Accordingly, the present invention is a method of reducing the growth of one or more neoplastic gastrointestinal cancer cells of a subject, the subject in need thereof, 3,8-dihydroxyeicosanoic acid, 1- (3). , 8-dihydroxyeicosanoyl) glycerol, 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol, 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol, 1- (3,8) -Dihydroxyeicosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol, 3,8-dihydroxyeicosanoic acid methyl ester, 3,8- Dihydroxyheneicosanoic acid, 1- (3,8-dihydroxyheneicosanoyl) glycerol, 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol, 1- (3,8-dihydroxyheneicosa) Noyl) 3-acetoxyglycerol, 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol, 3,8-Dihydroxyheneicosanoic acid methyl ester, 3,8-dihydroxydocosanoic acid, 1- (3,8-dihydroxydocosanoyl) glycerol, 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol, 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol, 1- (3,8-diacetoxydokosanoyl) 2,3 -A method comprising administration of an effective amount of a compound selected from the group consisting of diacetoxyglycerol and 3,8-dihydroxydocosanoic acid methyl ester.

Another aspect is a method of inducing apoptosis of one or more neoplastic epithelial cells, or a method of regulating the growth of one or more neoplastic epithelial cells (eg, one or more in vitro or exvivo). A method for regulating the proliferation of neoplastic epithelial cells), wherein the cells of one or more species and the compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof or a) 3, 8-Dihydroxyeikosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable The present invention relates to a method comprising contacting an effective amount of a compound selected from any one or more of the group consisting of salts or solvates.

（式（Ｉ）中、
Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５はそれぞれ独立してＨまたはアセチル（ＣＨ_３ＣＯ－）であり、
Ｒ_６はＨまたはＣＨ_３であり、Ｒ_７はＣＨ_３またはＣ２～Ｃ６の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して３～１４の整数であり、
但し、Ｒ_６がＨである場合にはｘ＋ｙは１０超且つ１８以下であり、Ｒ_６がＣＨ_３である場合にはｘ＋ｙは９超且つ１７以下である）
の化合物またはその薬学的に許容される塩もしくは溶媒和物の治療上有効な量を含み、から本質的になり、またはなる組成物に関する。 In a further aspect, the invention is a composition for use in the treatment or prevention of a subject epithelial cancer, according to formula (I) :.

(In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less).
With respect to a composition comprising, and essentially consisting of, a therapeutically effective amount of a compound of or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, X = 4, R ₆ = H, and y = 9, 10, 11, 12 or 13.

For example, x = 4, R ₄ , R ₅ and R ₆ = H, and y = 10, 11 or 12.

Accordingly, in another aspect, the invention relates to at least one compound as defined herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or a) 3, 8-Dihydroxyeikosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable With respect to an anti-epithelial cancer composition comprising or consisting essentially of a compound selected from any one or more of the group consisting of salts or solvates.

In another aspect, the invention relates to at least one compound as defined herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or a) 3,8-. Dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable With respect to a pharmaceutical composition comprising or consisting essentially of a compound selected from any one or more of the group consisting of salts or solvates).

In one aspect, the composition is for use in the treatment or prevention of epithelial cancer.

In one aspect, the composition is for maintaining or improving the health of the skin.

In one aspect, the composition is for maintaining or improving the health of the gastrointestinal tract.

In another aspect, the invention inhibits epithelial tumor formation (preferably skin tumor formation) of a subject, inhibits epithelial tumor growth (preferably skin tumor growth), and causes epithelial tumor metastasis (preferably skin tumor metastasis). A method of inhibiting or treating or preventing epithelial cancer (preferably skin cancer), wherein at least one compound as defined herein (eg, a compound of formula (I) or) to the subject in need. A therapeutically effective amount of the pharmaceutically acceptable salt or admixture) or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable A separate effective amount of a composition consisting of or consisting essentially of, comprising a therapeutically effective amount of at least one compound selected from any one or more of the group consisting of salts or solvates. Containing methods involving simultaneous or continuous administration of.

Another aspect is a method of increasing a subject's responsiveness to the treatment of epithelial cancer, the therapeutically effective amount of the compound of formula (I) to this subject or the compound a described herein. A composition comprising a therapeutically effective amount of at least one compound selected from any one or more of u) or a pharmaceutically acceptable salt or solvate thereof or described herein. The present invention relates to a method comprising administration of an effective amount of a composition.

In one aspect, this epithelial cancer treatment is a gastrointestinal cancer treatment. For example, this gastrointestinal cancer treatment is colorectal cancer treatment, throat cancer treatment, cheek cancer treatment or gastric cancer treatment.

In one aspect, the invention relates to a method of increasing the responsiveness of a subject to the treatment of skin cancer, comprising administering to the subject the composition described herein.

In one aspect, this skin cancer treatment is a basal cell carcinoma treatment. In another aspect, this skin cancer treatment is a squamous cell carcinoma treatment. In a further aspect, this skin cancer treatment is a melanoma treatment.

Another aspect is a method of increasing the sensitivity of a subject's epithelial tumor to the treatment of epithelial cancer, the therapeutically effective amount of the compound of formula (I) to this subject or the compound described herein. A composition comprising a therapeutically effective amount of at least one compound selected from any one or more of a) to u) or a pharmaceutically acceptable salt or solvate thereof or described herein. It relates to a method comprising administration of an effective amount of the composition being made.

Another aspect is a method of sensitizing one or more epithelial cancer cells that are resistant to treatment, a therapeutically effective amount of a compound of formula (I) or described herein. An effective amount of a composition comprising a therapeutically effective amount of at least one compound selected from any one or more of the compounds a) to u) or a pharmaceutically acceptable salt or solvate thereof. Contains to methods including administration of.

In one aspect, this epithelial tumor is a gastrointestinal tumor. For example, this gastrointestinal tumor is a colonic rectal tumor, a throat tumor, a buccal tumor or a gastric tumor.

In one aspect, the invention relates to a method of increasing the sensitivity of a subject's skin tumor to cancer treatment, comprising administration of the composition described herein to this subject.

In one aspect, this skin tumor is a basal cell carcinoma. In another aspect, the skin tumor is a squamous cell carcinoma. In a further aspect, this skin tumor is melanoma.

In a further aspect, the invention is a method of increasing susceptibility to treat one or more epithelial cancer cells that are resistant to treatment, the formula for this one or more epithelial cancer cells. It relates to a method comprising administering an effective amount of a compound of (I) or a pharmaceutically acceptable salt or solvate thereof or an effective amount of the composition described herein.

In one aspect, the epithelial cancer cells include a tumor present in the subject.

In one aspect, the invention is a method of increasing the sensitivity of one or more epithelial cancer cells (preferably skin cancer cells) that are resistant to treatment, the one or more epithelial cancer cells. (Preferably skin cancer cells) are administered with an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or an effective amount of the composition described herein. Including that.

In one aspect, the skin cancer cells include a tumor present in the subject.

The present invention is also a method for at least partially reversing the resistance of a subject's tumor cells suffering from epithelial cancer to the treatment of epithelial cancer, wherein the compound of formula (I) or a pharmaceutical thereof to this subject is also used. A therapeutically effective amount of a salt or solvate permissible or at least one compound selected from any one or more of the compounds a) to u) described herein, or pharmaceuticals thereof. Also related to a composition comprising a therapeutically effective amount of an acceptable salt or solvate or a method comprising administration of an effective amount of the composition described herein.

In one aspect, the method is a method of at least partially reversing the resistance of a subject's tumor cells suffering from skin cancer to cancer treatment, the compound of formula (I) or a compound thereof to this subject. A method comprising administration of a pharmaceutically acceptable salt or solvate or an effective amount of the composition described herein.

The invention further comprises a method of completely or partially reversing the resistance of a patient suffering from epithelial cancer (preferably suffering from skin cancer) to epithelial cancer treatment (preferably skin cancer treatment). Therapeutically effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof or any of the compounds a) to u) described herein for the patient. A composition comprising a therapeutically effective amount of at least one compound selected from one or more or a pharmaceutically acceptable salt or admixture thereof or an effective amount of the composition described herein. The present invention relates to a method comprising the step of administering.

In another aspect, the invention is one or more of a patient suffering from epithelial cancer who exhibits or is expected to exhibit or will become resistant to treatment with epithelial cancer treatment. A method of increasing the susceptibility of a tumor to treatment with epithelial cancer, therapeutically effective amounts or herein of a compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof for said patient. A composition comprising a therapeutically effective amount of at least one compound selected from any one or more of the compounds a) to u) described in, or a pharmaceutically acceptable salt or admixture thereof. Alternatively, a method comprising the step of administering an effective amount of the composition described herein is provided.

In one aspect, this method is for one or more tumors of a patient suffering from skin cancer that is resistant to, or is expected to be resistant to, treatment with skin cancer treatment. , A method of increasing susceptibility to treatment with skin cancer treatment, to the patient, the compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof or the composition described herein. A method comprising the step of administering an effective amount.

In one aspect, the tumor is resistant to treatment with chemotherapeutic agents.

In one aspect, the subject is a human. In a further aspect, the invention is a method of improving skin health or gastrointestinal health, wherein the subject in need is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof or It relates to a method comprising administering an effective amount of the composition described herein.

In one aspect, the composition is a synergistic therapeutic composition. In one aspect, the composition provides a synergistic therapeutic effect.

In one aspect, the composition is at least one that provides a greater synergistic therapeutic effect with the compounds described herein with a greater synergistic therapeutic effect compared to the effect of only one or the additive effect of only one. Includes additional remedies and. For example, for induction of apoptosis, survival or proliferation of epithelial cancer cells (eg, survival or proliferation of skin cancer cells), susceptibility to treatment, treatment or prevention of epithelial cancer (eg, skin cancer), or methods of treatment. Greater effect on subject or tumor responsiveness. Without wishing to be bound by theory, we suggest that this enhanced effect may result from improved bioavailability of the composition, for example by improved water dispersibility. think. In one aspect, administration of co- or serially administered epithelial cancer treatments (eg, skin cancer treatments) with this compound or at least one additional therapeutic agent reduces the dose or length of administration as needed. Or increase.

In one aspect, the composition (eg, a synergistic therapeutic composition) comprises at least one additional compound or extract derived from poplar-derived propolis. For example, the composition further comprises at least one compound selected from the group comprising pinocembrin, CAPE, chrysin, pinostrobin chalcone, galangin, benzyl caffeate, benzyl ferulate or caffeic acid.

Another aspect is at least one compound as defined herein (eg, a compound of formula (I) or pharmaceutically thereof) in the manufacture of a drug or composition for the purposes described herein. Acceptable salt or solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable A compound selected from any one or more of the group consisting of salts or solvates).

In one aspect, this use is in combination with at least one additional therapeutic agent in the manufacture of a drug or composition for the purposes described herein.

Another aspect is at least one compound as defined herein (eg, a compound of formula (I) or pharmaceutically thereof) in the manufacture of a drug or composition for the purposes described herein. Acceptable salt or solvate or a) 3,8-dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydocosanoic acid methyl ester or a) to u) are pharmaceutically acceptable. Use with at least one additional therapeutic agent of a composition comprising (a compound selected from any one or more of the group consisting of salts or solvates), wherein the drug or composition is this. With respect to use, which is formulated for separate, simultaneous or continuous administration of at least one compound and at least one additional therapeutic agent.

In one aspect, the drug or composition comprises cyclodextrin. In one aspect, the drug or composition comprises one or more dihydroxy fatty acid compounds described herein (eg, compounds of formula (I) complexed with cyclodextrin).

In another embodiment, the compound is dissolved in a solvent or a mixture of solvents (eg, ethanol, ethanol / water, propanol, propanol / water, isopropanol, isopropanol / water, ethyl acetate, hydrocarbon solvent, edible oil or propylene glycol). Will be provided.

In one aspect, the drug or composition is
a) 3,8-Dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester or a) to any one of u) pharmaceutically acceptable At least one compound selected from any one or a plurality of the group consisting of salts or solvates is added.

Another aspect relates to the composition for use below: inhibition of epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer in human subjects; one of human subjects or Induction of apoptosis in multiple neoplastic epithelial cells; Increased responsiveness of human subjects to treatment of epithelial cancer; Increased sensitivity of epithelial tumors in human subjects to treatment of epithelial cancer; Or to increase the susceptibility of multiple types of epithelial cancer cells; at least a partial reversal of resistance to epithelial cancer treatment of tumor cells in human subjects suffering from epithelial cancer; in human patients suffering from epithelial cancer. Complete or partial reversal of resistance to epithelial cancer treatment; or suffering from epithelial cancer that is or is expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment. To increase the susceptibility of one or more tumors in human patients to treatment with epithelial cancer treatment.

In one aspect, the composition is for use in: inhibition of skin tumor formation, inhibition of skin tumor growth, inhibition of skin tumor metastasis or treatment or prevention of skin cancer in human subjects; one of human subjects. Or induction of apoptosis of multiple neoplastic skin cells; increased responsiveness of human subjects to skin cancer treatment; increased sensitivity of skin tumors in human subjects to skin cancer treatment; 1 of human subjects who are resistant to treatment Increasing the susceptibility of a species or multiple types of skin cancer cells; at least a partial reversal of the resistance of tumor cells in human subjects suffering from skin cancer to skin cancer treatment; in human patients suffering from skin cancer Complete or partial reversal of resistance to skin cancer treatment; or suffering from skin cancer that is or is expected to be resistant or expected to be resistant to treatment with skin cancer treatment. To increase the susceptibility of one or more tumors of a human patient to treatment with skin cancer treatment.

In one example, the invention relates to a composition for use in the treatment or prevention of skin cancer.

In one aspect, the composition further comprises cyclodextrin.

In one aspect, the composition further comprises propolis (eg, poplar-derived propolis).

In one aspect, the composition further comprises an extract derived from poplar (eg, a poplar leaf or bud exudate as described in the examples herein).

In various embodiments, the composition comprises propolis (eg, poplar-derived propolis, eg, propolis extract or fraction, propolis resin, propolis resin extract and / or poplar-derived extract), the propolis, propolis. Resins, propolis resin extracts and / or poplar-derived extracts are rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. There is.

In one aspect, the composition further comprises propolis, a propolis resin or a propolis resin extract, and cyclodextrin.

In one aspect, the cyclodextrin is alpha-cyclodextrin.

In one aspect, the cyclodextrin is beta-cyclodextrin.

In one aspect, the cyclodextrin is gamma-cyclodextrin.

In one aspect, the cyclodextrin is hydroxypropyl beta-cyclodextrin.

In one aspect, the cyclodextrin is hydroxypropyl gamma-cyclodextrin.

In one aspect, the cyclodextrin is a mixture of cyclodextrins.

In one aspect, the anti-skin cancer composition is an anti-basal cell carcinoma composition. In another aspect, the anti-skin cancer composition is an anti-flat epithelial cell carcinoma composition. In a further aspect, this anti-skin cancer composition is an anti-melanoma composition.

In another aspect, the invention is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. With respect to a pharmaceutical composition comprising, essentially consisting of, or consisting of.

In one aspect, the composition comprises propolis, a propolis resin or a propolis resin extract and a compound of one or more of formula (I) or a pharmaceutically acceptable salt or solvate thereof. The composition comprises, for example, a propolis to which one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof have been added. Includes propolis resin or propolis resin extract. In another aspect, the composition is a bud of propolis and / or poplar rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Alternatively, it comprises a fraction from a leaf exudate, a propolis resin or a propolis resin extract.

In one aspect, this propolis is poplar-derived propolis.

In one aspect, the composition further comprises cyclodextrin.

In one aspect, the composition is for maintaining or improving the health of the skin. Accordingly, in one aspect, the invention is a pharmaceutical composition for maintaining or improving the health of the skin, wherein one or more compounds of formula (I) or one or more pharmaceuticals thereof. Containing, comprising, and essentially consisting of propolis, propolis resin or propolis resin extract rich in salts or solvates, and cyclodextrin.

In one aspect, the propolis rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof is a propolis resin, eg, a poplar-derived propolis resin. be. In one aspect, the resin is a propolis resin (eg, a poplar-derived propolis resin), the cyclodextrin being alpha, beta or gamma-cyclodextrin.

In another aspect, the invention is a method of treating or preventing a subject's skin cancer, a method of inhibiting skin tumor formation, a method of inhibiting skin tumor growth or inhibiting skin tumor metastasis, one or more of the subjects. How to induce apoptosis of neoplastic skin cells, how to regulate the growth of one or more neoplastic skin cells in a subject, how to increase the subject's responsiveness to skin cancer treatment, subjects to skin cancer treatment A method of increasing the sensitivity of a skin tumor, a method of increasing the sensitivity of one or more skin cancer cells that are resistant to treatment, to the required subject or one or more of these cells. I) Containing propolis, propolis resin or propolis resin extract and cyclodextrin rich in one or more compounds or one or more pharmaceutically acceptable salts or admixtures thereof. Consistent with methods comprising administering an effective amount of a composition consisting of or consisting of.

In one aspect, this apoptosis is for skin tumor cells (eg, basal carcinoma cells, squamous cell carcinoma cells or melanoma cells).

In one aspect, this adjustment is reduced. Accordingly, the present invention is a method of reducing the proliferation of one or more neoplastic skin cells of a subject, the compound of one or more of formula (I) or one thereof to a required subject. Administration of an effective amount of a composition consisting essentially of or consisting of a species or pharmaceutically acceptable salt or solvate-rich propolis, propolis resin or propolis resin extract and cyclodextrin. Regarding methods including.

In one aspect, this proliferation is for skin tumor cells (eg, basal cell carcinoma cells, squamous cell carcinoma cells or melanoma cells).

In one aspect, the skin cancer cells include a tumor present in the subject. In one aspect, the skin cancer cells are basal cancer cells. In another aspect, the skin cancer cells are squamous cell carcinoma cells. In a further aspect, the skin cancer cells are melanoma cells.

The present invention is also a method of at least partially reversing the resistance of a subject's tumor cells suffering from skin cancer to treatment for skin cancer, wherein one or more of formula (I) to this subject. A composition comprising or consisting of propolis, a propolis resin or a propolis resin extract and cyclodextrin, which is rich in a pharmaceutically acceptable salt or admixture of the compound or one or more of the above. It also relates to methods involving administration.

The present invention further comprises a method of completely or partially reversing the resistance of a patient suffering from skin cancer to the treatment of skin cancer, wherein the patient is given one or more compounds of formula (I). Or administer a composition consisting essentially of or comprising propolis, a propolis resin or a propolis resin extract and cyclodextrin, which is rich in one or more pharmaceutically acceptable salts or solvents thereof. Concerning methods involving steps.

In another aspect, the invention is one or more of a patient suffering from skin cancer who is resistant to, or is expected to be resistant to, or is expected to become resistant to treatment with skin cancer treatment. A method for increasing the susceptibility of a type of tumor to a patient, propolis rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or admixtures thereof. , A method comprising the step of administering a composition comprising or consisting essentially of, comprising, a propolis resin or a propolis resin extract and cyclodextrin.

In one aspect, the one or more tumors have increased activation of one or more precancerous cell survival signaling pathways within or within the one or more tumors (eg, patient). Due to increased activation of one or more of the AKT, JNK or JAK / STAT signaling pathways within a sample from (eg, tissue sample, tumor biopsy, or blood or plasma sample). It is expected to be resistant to, or will be resistant to, or will become resistant to cancer treatment.

In one aspect, the invention provides a method of inactivating or suppressing one or more precancerous cell survival signaling pathways within one or more tumors or within a patient. For example, the present invention relates to a method of inactivating or suppressing one or more of the AKT, JNK or JAK / STAT signaling pathways in one or more tumors.

In one aspect, the one or more tumors are associated with increased activation of one or more of the AKT, JNK or JAK / STAT signaling pathways within the tumor for the treatment of skin cancer. Is expected to show resistance, or show resistance or become resistant.

In one aspect, the invention is a method of preventing a tumor from becoming resistant to the treatment of primary skin cancer, wherein the resistance is, for example, an AKT, JNK or JAK / STAT signal within the tumor. Provided is a method that is at least partially mediated by an increase in activation of one or more of the transmission pathways.

In one aspect, the tumor is resistant to treatment with chemotherapeutic agents.

In one aspect, this skin cancer is a basal cell carcinoma. In another aspect, this skin cancer is a squamous cell carcinoma. In a further aspect, this skin cancer is melanoma.

In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or admixtures thereof. Containing, and containing alpha-cyclodextrin (eg, poplar-derived propolis, propolis resin or propolis resin extract, and cyclodextrin, such as poplar-derived propolis and alpha-cyclodextrin). , Or consists of.

In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or admixtures thereof. Compounds and beta-cyclodextrin (eg, poplar-derived propolis, propolis resin or propolis resin extract, such as poplar-derived propolis, propolis resin or propolis resin extract and beta-cyclodextrin, and cyclodextrin). Includes, consists of, or consists of.

In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or admixtures thereof. Compounds and gamma-cyclodextrin (eg, poplar-derived propolis, propolis resin or propolis resin extract, such as poplar-derived propolis, propolis resin or propolis resin extract and gamma-cyclodextrin, and cyclodextrin). Includes, consists of, or consists of.

In a further aspect, the invention is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof. To provide a synergistic composition comprising and cyclodextrin. In one aspect, the composition is a synergistic therapeutic composition. In one aspect, the composition provides a synergistic therapeutic effect.

In one embodiment, a propolis, a propolis resin or a propolis resin extract and a cyclodextrin rich in one or more compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Provides a greater synergistic therapeutic effect compared to the effect of only one or the additive effect of only one. For example, it has a greater effect on the subject or tumor responsiveness to induction of apoptosis, survival or proliferation of skin cancer cells, susceptibility to treatment, treatment or prevention of skin cancer, or treatment methods. In one aspect, a propolis, propolis resin or propolis resin extract and cyclodextrin rich in one or more compounds of formula (I) or a pharmaceutically acceptable salt or admixture thereof of one or more of them. Depending on the co- or serial administration of skin cancer treatment, the dose or length of administration may be reduced or increased as needed.

Another aspect is the compound of one or more of formula (I) or the pharmaceutically acceptable salt of one or more thereof in the production of the compositions for the purposes described herein. Alternatively, it relates to the use of cyclodextrin with propolis, propolis resin or propolis resin extract rich in solvates.

Another aspect is the compound of one or more of formula (I) or the pharmaceutically acceptable salt of one or more thereof in the production of the compositions for the purposes described herein. Alternatively, it relates to the use of a solvent-rich propolis, propolis resin or propolis resin extract with cyclodextrin in combination with at least one additional therapeutic agent. In one aspect, this use is for abundant propolis, propolis resin or propolis resin extract and alpha-cyclodextrin. In one aspect, this use is for abundant propolis, propolis resin or propolis resin extract and beta-cyclodextrin. In one aspect, this use is for abundant propolis and gamma-cyclodextrin.

Another aspect of the invention is the pharmaceutically acceptable one or more compounds of formula (I) or one or more thereof in the preparation of the compositions for the purposes described herein. The composition is used in combination with at least one additional therapeutic agent of a complex containing propolis, propolis resin or propolis resin extract and cyclodextrin, which is rich in salt or solvent. Concerning the use of a complex of propolis, propolis resin or propolis resin extract and cyclodextrin and formulated for separate, simultaneous or continuous administration of at least one therapeutic agent.

Another aspect is rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof for use in improving skin health. With respect to a composition comprising or consisting essentially of, including, propolis, propolis resin or propolis resin extract and cyclodextrin. In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Containing, consisting of, or consisting of a substance and alpha-cyclodextrin. In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Containing, consisting of, or consisting of a substance and gamma-cyclodextrin.

In another aspect, the invention is pharmaceutically acceptable of one or more compounds of formula (I) or one or more thereof for use in the treatment or prevention of a subject's skin cancer. It relates to a composition comprising or consisting essentially of a propolis, a propolis resin or a propolis resin extract rich in salt or solvate, and cyclodextrin. In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Containing, consisting of, or consisting of a substance and alpha-cyclodextrin. In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Containing, consisting of, or consisting of a substance and gamma-cyclodextrin.

Another aspect is one or more compounds of formula (I) or compounds thereof as a composite preparation for simultaneous, separate or continuous use for the purposes described herein. Propolis, propolis resin or propolis resin extract rich in one or more pharmaceutically acceptable salts or solvents, cyclodextrin and optionally one or more, two or more or three. With respect to products consisting of or consisting essentially of, including the above additional therapeutic agents.

Another aspect relates to compositions for use in the treatment or prevention of skin cancer.

One aspect is a method of isolating or purifying a compound of formula (I) or a mixture of compounds of formula (I) from propolis or poplar, propolis resin or extracts or exudates thereof.
The steps of preparing poplar, propolis, propolis resin or extracts or exudates thereof, and isolating or purifying this compound or mixtures of this compound from this poplar, propolis, propolis resin or extracts or exudates thereof. Concerning methods involving steps.

In various embodiments, the method comprises one or more of the following non-limiting steps:
a) Chromatography (eg, column chromatography, reverse phase chromatography, normal phase chromatography or supercritical fluid chromatography) and / or solvent fractionation of this poplar, propolis, propolis resin or extracts or exudates thereof. Partitioning) and / or fractionation by supercritical extraction to obtain one or more fractions comprising one or more of the compounds of formula (I).
b) The compound of formula (I) is obtained by fractionating this poplar, propolis, propolis resin or extract or admixture thereof or one or more fractions by preparative HPLC and / or polymer resin fraction. A step of obtaining one or more fractions comprising one or more of these, and optionally c) a step of further purifying the compound of formula (I) from one or more fractions of step b), and / Or a step of further purifying the compound of formula (I) from one or more fractions of step c).

In a further embodiment, the poplar, propolis, propolis resin or extract or exudate is subjected to a hydrolysis reaction, a methylation reaction or an acetylation reaction, followed by one or more of steps a), b) or c). It is possible to carry out isolation and purification of one or more compounds of formula (I).

A further aspect relates to a marker of anti-epithelial cancer effect comprising a compound of formula (I).

Another aspect is the method of assessing the anti-epithelial cancer effect of a composition or product.
a) Preparing a sample of this composition or product, and b) any of the following:
i) Determining the presence of one or more compounds of formula (I) in this sample,
Or ii) measure the amount and / or concentration of one or more compounds of formula (I) in this sample and one or more of this one or more compounds in this sample. Determining if the amount and / or concentration is greater than or equal to the reference amount of a compound known to have an antiepithelial cancer effect, and optionally.
iii) In vitro or in vivo bioassays relating to methods comprising determining the biological activity of this compound and / or fractions containing this compound.

A further aspect is the method of assessing the anti-epithelial cancer effect of a composition or product.
a) Receiving information about the presence and / or amount of one or more compounds of formula (I) in a sample of this composition or product, and b) the amount of each compound in this sample. It relates to a method comprising determining whether or not the amount of a compound known to have an antiepithelial cancer effect is greater than or equal to a reference amount.

A further aspect is the method of assessing the anti-epithelial cancer effect of a composition or product.
a) Confirm the presence and / or amount of one or more compounds of formula (I) in the sample of this composition or product using gas chromatography, liquid chromatography or supercritical fluid chromatography. And b) a method comprising determining whether the amount of each compound in this sample is greater than or equal to a reference amount of a compound known to have an anti-epithelial cancer effect.

In various embodiments, the method of assessing the antiepithelial cancer effect of this composition or product comprises one or more of the following steps:
a) Fractionation of this sample by solvent splitting and / or supercritical fluid extraction and / or chromatography (eg reverse phase chromatography) to one or more of the compounds of formula (I). Or the process of obtaining multiple fractions,
b) Further fractionation of one or more fractions rich in one or more of the compounds of this formula (I) by one or more of solvent extraction or supercritical fluid extraction or chromatography. , A step of obtaining one or more fractions very rich in one or more of the compounds of formula (I),
c) One of the compounds of formula (I) in this sample is analyzed for this very rich fraction by one or more of gas chromatography, liquid chromatography or supercritical chromatography, for example. The step of determining the presence and / or amount of a species or multiple species.

In various embodiments, the method of assessing the antiepithelial cancer effect of this composition or product comprises one or more of the following steps:
a. A step of fractionating a sample by chromatography (eg, reverse phase chromatography) to obtain one or more chromatographic fractions.
b. A step of fractionating this sample or chromatographic fraction by preparative HPLC to obtain one or more HPLC fractions.
c. The step of analyzing the traces produced by preparative HPLC to determine the presence and / or amount of compound in this sample, and / or d. The sample, one or more reverse chromatographic fractions or one or more HPLC fractions are subjected to mass spectrometry for the presence and / or amount of one or more compounds of formula (I) in this sample. The process of determining.

In one aspect, determination of the presence and / or amount of one or more of the compounds of formula (I) in this sample is by mass spectrometry (eg, liquid chromatography-mass spectrometry (LC-MS)).

In one aspect, the invention is a composition or product comprising one or more compounds of formula (I), wherein the amount and / or concentration of one or more compounds of formula (I) is. With respect to the composition or product specified on the label associated with this composition or product (eg, but not limited to product labels, certificates of analysis, websites, promotional materials).

In various embodiments, the compound of formula (I) is
a) 3,8-Dihydroxyeicosanoic acid,
b) 1- (3,8-dihydroxyeicosanoyl) glycerol,
c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
g) 3,8-Dihydroxyeicosanoic acid methyl ester,
h) 3,8-dihydroxyheneicosanoic acid,
i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
n) 3,8-Dihydroxyheneicosanoic acid methyl ester,
o) 3,8-dihydroxydocosic acid,
p) 1- (3,8-dihydroxydocosanoyl) glycerol,
q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
It is selected from the group consisting of t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and u) 3,8-dihydroxydokosanoic acid methyl ester.

In one aspect, the composition or product is or comprises propolis, propolis resin or propolis extract, eg, propolis, propolis resin or propolis resin comprising or abundant in one or more compounds of formula (I). Is or contains an extract.

In one aspect, the label associated with this composition or product is a label or packaging insert.

In one aspect, the label associated with this composition or product is a Certificate of Analysis (COA).

In one aspect, the label associated with this composition or product is a website promoting this product.

In one aspect, the label associated with this composition or product is a booklet or pamphlet promoting this product.

The following aspects may relate to any of the above aspects.

In various aspects, the epithelial cancer is epithelial cancer or similar epithelial cancer.

In various embodiments, the epithelial cancer is gastrointestinal cancer, eg, colorectal cancer, throat cancer, esophageal cancer, cheek cancer or gastric cancer. For example, in one aspect, colorectal cancer is colon adenocarcinoma. In another aspect, esophageal cancer is squamous cell carcinoma of the esophagus. In another aspect, gastric cancer is gastric cancer.

In another aspect, the epithelial carcinoma is a skin cancer, eg, a basal cell carcinoma, a squamous epithelial cell carcinoma or a melanoma.

In various embodiments, the composition comprises caffeic acid phenyl ether ester (CAPE), caffeic acid, pinocembrin, benzyl caffeate, benzyl ferulate, benzyl isoferulate, chrysin, cinnamyl caffeate, pinostrobin chalcone, galangin and pinobanksin. Including one or more of them.

In an exemplary embodiment, the composition comprises CAPE, caffeic acid, pinocembrin, benzyl caffeate, benzyl ferulate, benzyl isoferulate, cinnamyl caffeate, pinostrobin chalcone, chrysin, galangin and pinobanksin-3-acetate. One or more of the above is added.

In one aspect, the composition has a CAPE concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, Higher than 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about 5, About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g) ..

In one aspect, the composition has pinocembrine concentrations of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, Higher than 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about 5, About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g) ..

In one aspect, the composition has a galangin concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, Higher than 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about 5, About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g) ..

In one aspect, the composition has a chrysin concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, Higher than 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about 5, About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g) ..

In one aspect, the composition has a pinobanksin concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, Higher than 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about 5, About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g) ..

In one aspect, the composition has a caffeic acid concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100. , 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g and the effective range can be selected between any of these values (eg, about 1 to about 5). , About 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g ).

In one aspect, the composition has a benzyl caffeate concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, Higher than 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about). 5, about 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g).

In one aspect, the composition has a benzyl ferulate concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, Higher than 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about). 5, about 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g).

In one aspect, the composition has a cinnamyl caffeate concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, Higher than 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about). 5, about 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g).

In one aspect, the composition has a cinnamyl ferulate concentration of about 1, 2, 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, Higher than 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500 or 600 mg / g, the effective range can be selected between any of these values (eg, about 1 to about). 5, about 1 to about 10, about 2 to about 20, about 5 to about 20, about 5 to about 25, about 10 to about 25, about 10 to about 40, about 15 to about 100 or about 20 to about 600 mg / g).

In various embodiments, the cyclodextrin is an alpha-cyclodextrin, or the cyclodextrin is present as a combination of cyclodextrins, including alpha-cyclodextrin.

In various embodiments, the cyclodextrin is a beta-cyclodextrin, or the cyclodextrin is present as a combination of cyclodextrins, including beta-cyclodextrin.

In various embodiments, the cyclodextrin is a gamma-cyclodextrin, or the cyclodextrin is present as a combination of cyclodextrins, including gamma-cyclodextrin.

In one aspect, the cyclodextrin is a chemically modified cyclodextrin, an example of which is described in Stella and He, Cyclodextrins, Toxicology Pathology, 36, 2008, 30-42.

In one aspect, the chemically modified cyclodextrin is hydroxypropyl beta cyclodextrin or hydroxypropyl gamma cyclodextrin.

In one aspect, propolis is present in the antiepithelial cancer composition as an extract or fraction of propolis.

In one aspect, the propolis present in the antiepithelial cancer composition is wax-free. For example, this propolis has been derowned using an extraction process known in the art. Dewached propolis is often known or referred to as "propolis resin".

In one aspect, the propolis is "poplar-derived" propolis or "poplar" propolis. For example, "poplar-derived" propolis is at least partially derived from the bud and leaf exudates of one or more of poplar, birch, larch or willow.

In one aspect, the composition comprises from about 1.0% to about 99% by weight of propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I). In one aspect, the composition comprises from about 1.0% to about 99% by weight of propolis resin rich in one or more compounds of formula (I).

In various embodiments, the composition comprises from about 1% to about 99% by weight of propolis, propolis resin or propolis resin extract, 1 of formula (I), rich in one or more compounds of formula (I). About 1% to about 25% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of formula (I), about 1% by weight to about 30% by weight, rich in species or compounds. % Propolis, Propolis Resin or Propolis Resin Extract, About 1% to about 40% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of formula (I), formula (I) About 1% by weight to about 50% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of the formula (I), about 5% by weight to about 25% by weight of propolis, propolis resin or propolis resin extract, about 5% by weight to about 30% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of formula (I), formula ( About 5% by weight to about 40% by weight of propolis, propolis resin or propolis resin extract rich in one or more compounds of I), about 5% by weight rich in one or more compounds of formula (I) ~ About 50% by weight of propolis, propolis resin or propolis resin extract, about 5% by weight to about 99% by weight of propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I), About 10% to about 25% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of formula (I), about 10 rich in one or more compounds of formula (I) From% to about 30% by weight of propolis, propolis resin or propolis resin extract, about 10% to about 40% by weight of propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) Rich in product, one or more compounds of formula (I), about 10% by weight to about 50% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of formula (I) About 10% to about 99% by weight of propolis, propolis resin or propolis resin extract, about 15% to about 25% by weight of propolis, propolis resin or propolis rich in one or more compounds of formula (I) Resin extract, formula (I) About 15% by weight to about 30% by weight of propolis, propolis resin or propolis resin extract, rich in one or more compounds of the formula (I), about 15% by weight to about. 40% by weight of propolis, about 15% by weight to about 50% by weight of propolis rich in one or more compounds of formula (I), propolis resin or propolis resin extract, one or more of formula (I) About 15% by weight to about 99% by weight of propolis, propolis resin or propolis resin extract, about 20% by weight to about 25% by weight of propolis rich in one or more compounds of formula (I), Propolis resin or propolis resin extract, about 20% to about 30% by weight of propolis rich in one or more compounds of formula (I), propolis resin or propolis resin extract, one of formula (I) or About 20% to about 40% by weight of propolis rich in multiple compounds, propolis resin or propolis resin extract, about 20% to about 50% by weight rich in one or more compounds of formula (I). Propolis, propolis resin or propolis resin extract, about 20% to about 99% by weight of propolis, propolis resin or propolis resin extract, or formula (I) rich in one or more compounds of formula (I). About 25% by weight of propolis, propolis resin or propolis resin extract rich in one or more compounds, or about 30% by weight of propolis, propolis resin or propolis rich in one or more compounds of formula (I) Contains resin extract.

In various embodiments, the composition comprises from about 1% to about 99% by weight of a propolis resin rich in one or more compounds of formula (I), one or more compounds of formula (I). Rich from about 1% by weight to about 25% by weight of propolis resin, about 1% by weight to about 30% by weight of propolis resin rich in one or more compounds of formula (I), one or more of formula (I). About 1% by weight to about 40% by weight of a propolis resin rich in a species compound, about 1% by weight to about 50% by weight of a propolis resin rich in one or more compounds of the formula (I), of the formula (I). About 5% by weight to about 25% by weight of a propolis resin rich in one or more compounds, about 5% by weight to about 30% by weight of a propolis resin rich in one or more compounds of formula (I), formula. About 5% by weight to about 40% by weight of the propolis resin rich in one or more compounds of (I), about 5% by weight to about 50% by weight rich in one or more compounds of formula (I). Propolis resin, about 5% by weight to about 99% by weight, rich in one or more compounds of formula (I), about 10% by weight to about 10% by weight, rich in one or more compounds of formula (I). 25% by weight of propolis resin, about 10% by weight to about 30% by weight of propolis resin rich in one or more compounds of formula (I), about 10 rich in one or more compounds of formula (I) About 10% by weight to about 40% by weight of propolis resin, about 10% by weight to about 50% by weight of a propolis resin rich in one or more compounds of formula (I), one or more compounds of formula (I). About 10% by weight to about 99% by weight of propolis resin, about 15% by weight to about 25% by weight of propolis resin rich in one or more compounds of formula (I), one of formula (I) or About 15% by weight to about 30% by weight of propolis resin rich in a plurality of compounds, about 15% by weight to about 40% by weight of a propolis resin rich in one or more compounds of the formula (I), formula (I). About 15% by weight to about 50% by weight of a propolis resin rich in one or more compounds of the above, about 15% by weight to about 99% by weight of a propolis resin rich in one or more compounds of the formula (I), About 20% by weight to about 25% by weight of a propolis resin rich in one or more compounds of the formula (I), about 20% by weight to about 30% by weight rich in one or more compounds of the formula (I). Propolis resin, about 20% by weight to about 40% by weight, rich in one or more compounds of the formula (I), about 20% by weight, rich in one or more compounds of the formula (I). About 50 About 20% by weight to about 99% by weight of propolis resin, rich in one or more compounds of formula (I), or about 25 rich in one or more compounds of formula (I). It comprises about 30% by weight of propolis resin, or about 30% by weight of propolis resin, rich in one or more compounds of formula (I).

In one aspect, the propolis, propolis resin or propolis resin extract in the composition is completely encapsulated in cyclodextrin.

In one aspect, the molar ratio of propolis, propolis resin or propolis resin extract to cyclodextrin in the composition is about 1.1 or less.

In one aspect, the propolis, propolis resin or propolis resin extract is a poplar-derived propolis, propolis extract or propolis resin extract.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxyeicosanoic acid and / or is rich in 3,8-dihydroxyeicosanoic acid. In one aspect, the propolis, propolis resin or propolis resin extract from this poplar comprises 1- (3,8-dihydroxyeicosanoyl) glycerol and / or 1- (3,8-dihydroxyeicosanoyl). Rich in glycerol. In one aspect, the propolis, propolis resin or propolis resin extract from this poplar comprises 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol and / or 1- (3,8-dihydroxyeico). Sanoyl) 2-rich in acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol and / or 1- (3,8-dihydroxyeico). Sanoyl) Rich in 3-acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol and / or 1- (3,8). -Dihydroxyeicosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol and / or 1- (3). 8-Diacetoxyeicosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxyeicosanoic acid methyl ester and / or is rich in 3,8-dihydroxyeicosanoic acid methyl ester. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxyheneikosanoic acid and / or is rich in 3,8-dihydroxyheneikosanoic acid. In one aspect, the propolis, propolis resin or propolis resin extract from this poplar comprises 1- (3,8-dihydroxyheneicosanoyl) glycerol and / or 1- (3,8-dihydroxyheneicosa). Noil) Rich in glycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol and / or 1- (3,8-dihydroxy). Heneikosanoyl) 2-rich in acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol and / or 1- (3,8-dihydroxy). Heneikosanoyl) Rich in 3-acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol and / or 1- (3). 8-Dihydroxyhenei cosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol and / or 1- (3). , 8-Diacetoxyhen Eikosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxyheneikosanoic acid methyl ester and / or is rich in 3,8-dihydroxyheneikosanoic acid methyl ester. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxydocosanoic acid and / or is rich in 3,8-dihydroxydocosanoic acid. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxydocosanoyl) glycerol and / or to 1- (3,8-dihydroxydocosanoyl) glycerol. Rich. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol and / or 1- (3,8-dihydroxydocosanoyl). ) 2-rich in acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol and / or 1- (3,8-dihydroxydocosanoyl). ) Rich in 3-acetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol and / or 1- (3,8-). Dihydroxydocosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and / or 1- (3,8). -Diacetoxydokosanoyl) Rich in 2,3-diacetoxyglycerol. In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract comprises 3,8-dihydroxydocosanoic acid methyl ester and / or is rich in 3,8-dihydroxydocosanoic acid methyl ester.

In one aspect, the poplar-derived propolis comprises any one or more of the compounds a) to u) described herein in an amount of about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg. About 2.5 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 7 .5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 75 mg / kg, about 100 mg / kg, About 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, 250 mg / kg, about 300 mg / kg, about 350 mg / kg, about 400 mg / kg, about 450 mg / kg, about 500 mg / kg, about It has a concentration of more than 550 mg / kg or about 600 mg / kg.

In some embodiments, the poplar-derived propolis, propolis resin or propolis resin extract is at least about 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5, 5, 5.5, 6, 7.5, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400 , 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg / g, any two or more of the compounds a) to u) described herein, 3 Having one or more or four or more, the effective range can be selected from any of these values (eg, about 1 to about 400, about 1 to about 100, about 5 to about 1000, about 5 to about 500, about). 5 to about 300 or about 5 to about 100). For example, in some embodiments, the poplar-derived propolis is 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol and 1- (3,8-) at a concentration of about 1 mg / g to 1000 mg / g. Dihydroxydocosanoyl) 3-acetoxyglycerol, or 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol and 1- (3,3) 8-Dihydroxyheneicosanoyl) 3-acetoxyglycerol, or 1- (3,8-dihydroxyeikosanoyl) 3-acetoxyglycerol, 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol and 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol It has one or more of 3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol and compounds a) to c), e) to j) or l) to u).

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 3,8-dihydroxyeicosanoic acid concentration of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg / g, about. 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5. 5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g , About 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, It is about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyeicosanoyl) glycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g, about. 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g , About 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, It is about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g. g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, About 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / G, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g. g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, About 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / G, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g, about 0. .5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / G, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g , About 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g, about 0.1 mg / g. 0.5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4. 5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / G, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 3,8-dihydroxyeicosanoic acid methyl ester concentration of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg / g. , About 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / G, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 3,8-dihydroxyheneikosanoic acid concentration of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg / g. About 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5 .5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g , About 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyheneicosanoyl) glycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g. About 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / G, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g , About 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg. / G, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g , About 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, About 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg. / G, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g , About 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, About 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g, about 0.1 mg / g. 0.5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4. 5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / G, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g. About 0.5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4 .5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg. / G, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a concentration of 3,8-dihydroxyheneicosanoic acid methyl ester of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg / g. g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, About 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / G, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 3,8-dihydroxydocosaic acid concentration of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg / g, about. 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5. 5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, about 50 mg / g , About 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, It is about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxydocosanoyl) glycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg. / G, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g , About 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, About 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g. , About 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / G, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol concentration of at least about 0.1 mg / g, about 0.5 mg / g. , About 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / G, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g, about 0. 5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g g, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g , About 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, It is about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol concentration of at least about 0.1 mg / g, about 0. .5 mg / g, about 1 mg / g, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / G, about 5 mg / g, about 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g g, about 40 mg / g, about 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g , About 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In one aspect, the poplar-derived propolis, propolis resin or propolis resin extract has a and 3,8-dihydroxydocosanoic acid methyl ester concentrations of at least about 0.1 mg / g, about 0.5 mg / g, about 1 mg. / G, about 1.5 mg / g, about 2 mg / g, about 2.5 mg / g, about 3 mg / g, about 3.5 mg / g, about 4 mg / g, about 4.5 mg / g, about 5 mg / g , About 5.5 mg / g, about 6 mg / g, about 7.5 mg / g, about 10 mg / g, about 15 mg / g, about 20 mg / g, about 25 mg / g, about 30 mg / g, about 40 mg / g, About 50 mg / g, about 75 mg / g, about 100 mg / g, about 125 mg / g, about 150 mg / g, about 175 mg / g, about 200 mg / g, 250 mg / g, about 300 mg / g, about 350 mg / g, about 400 mg / g, about 450 mg / g, about 500 mg / g, about 550 mg / g or about 600 mg / g.

In various embodiments, the poplar-derived propolis, propolis resin or propolis resin extract comprises CAPE, chrysin, galangin, pinocembrin, pinocembrin, benzyl caffeate, benzyl ferulate, benzyl isoferlate, cinnamyl caffeate, cinnamyl ferulate, It further comprises any combination of two or more of pinocembrin chalcone and caffeic acid.

In various embodiments, the composition comprises at least one additional therapeutic agent, or is administered separately, simultaneously or sequentially with the therapeutic agent, preferably the at least one additional therapeutic agent is anti. A tumor agent, preferably the antitumor agent, is selected from anti-tumour food factor, chemotherapeutic agents or immunotherapeutic agents.

In various embodiments, skin cancer treatments, therapeutic agents or antitumor agents are effective in inducing apoptosis, eg, in one or more skin cancer cells or in one or more tumor cells. It is effective for.

In one aspect, the composition is a consumer good.

In one aspect, the composition is a composition for topical administration.

In one aspect, the topical composition is one or more penetrants, photoprotectants, UV protectants, vitamins, moisturizers, oils, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic. Includes activators, preservatives, antioxidants, solvents, fragrances, excipients, pigments, odor absorbers or pigments.

In one aspect, the composition is a food, beverage, food additive, beverage additive, nutritional supplement, nutritional product, medical food, functional food, drug or pharmaceutical.

In various embodiments, the composition is formulated for oral administration, topical administration or parenteral administration.

In one aspect, the composition formulated for oral administration comprises gamma-cyclodextrin.

In one aspect, the composition formulated for topical administration comprises alpha-cyclodextrin.

In one aspect, the composition formulated for topical administration comprises beta-cyclodextrin.

In one aspect, the composition comprises one or more additional anti-epithelial cancer agents.

In one aspect, the composition is a pharmaceutical composition.

In various embodiments, the chemotherapeutic agent is selected from the group comprising: thread division inhibitors such as binca alkalolides such as vincristine, vinblastin, binorelbin, bindesin, vinflunin, podophilotoxin, taxan, eg. Docetaxel, larotaxel, altertaxel, paclitaxel and tesetaxel, and epotiron, eg ixabepyrone; topoisomerase I inhibitors such as topotecan, irinotecan, camptothecin, rubitecan and verotecan, topoisomerase type II inhibitors such as amsacrine Cyclones such as acralbisin, downorbisin, doxorubicin, epirubicin, idalbisin, amrubicin, pirarubicin, valrubicin and sorbicin, and anthracendions such as mitoxanthron and pixantron; metabolic antagonists such as dihydrofolate reductase inhibitors such as aminopterin, methotrexate. , Timidylic acid synthase inhibitors such as lartitrexed and pemetrexed, adenosine deaminase inhibitors such as pentostatin, halogenated or ribonucleotide reductase inhibitors such as cladribine, clofarabin and fludarabin, thiopurines such as thioguanine and mercaptopurine, thymidylate synthase inhibitors For example, fluorouracil, capesitabin, tegafur, carmofur and floxuridine, DNA polymerase inhibitors such as citarabin, ribonucleotide reductase inhibitors such as gemcitabine, hypomethyllating agents such as azacitidine and decitabin, and ribonucleotide reductase inhibition. Agents such as hydroxyureas; cell cycle non-specific antineoplastic agents such as alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, iphosphamide, trophosphamide, chlorambusyl, merphalan, prednimustin, bendamstin, uramstin (Uramustine), estramstin, nitrosourea such as carmustin, romstin, semstin, fotemstin, nimustin, lanimustin and streptosocin, alkyl sulfonates such as busulfan, mannosulfan and g. Leosulfane, aziridines such as carbocon, thioTEPA, triazicon and triethylenemelamine, alkylation-like agents such as platinum agents such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, satraplatin, hydrazine such as procarbazine, triazene, For example dacarbazine, temozolomid, altretamine and mitobronitol, and streptomycins such as actinomycin, bleomycin, daunomycin, mitomycin and plicamycin; photosensitizers such as aminolevulinic acid, methyl aminolevulinate, ephaproxial, and porphyrin derivatives such as porphymer sodium. , Talaporfin, temoporfin and verteporfin; enzyme inhibitors such as farnesyltransferase inhibitors such as tipifarnib, cyclin-dependent kinase inhibitors such as arbosidib and seliciclib, proteasome inhibitors such as voltezomib, phosphodiesterase inhibitors such as anagrelide. , IMP dehydrogenase inhibitors such as thiazofulin, lipoxygenase inhibitors such as massoprocol, and PARP inhibitors such as olaparib; receptor antagonists such as endoserin receptor antagonists such as atlascentan, retinoid X receptor antagonists such as bexaloten and test lactone; and other Chemotherapeutic agents such as amsacrine, travectedin, retinoids such as alitretinoin and tretinone, arsenic trioxide, asparagine depleter, such as asparaginase or pegaspargase, seliciclib, demecortin, elesculomol, elesculomol, elesclomol. And Ronidamine.

References to the range of numbers disclosed herein (eg 1-10) also refer to all rational numbers within this range (eg 1, 1.1, 2, 3, 3.9, 4, 5, 6). , 6.5, 7, 8, 9 and 10) and references to any range of rational numbers within this range (eg 2-8, 1.5-5.5 and 3.1-4.7). Accordingly, it is intended thereby expressly disclosing all subscopes of all scopes expressly disclosed herein. These are merely examples of what is specifically intended and all possible combinations of numbers between the listed minimum and maximum values are explicitly stated in this application in a similar manner. Should be considered.

In the present specification referring to a patent specification, other external document or other source of information, this is generally intended to provide a context for discussing the features of the invention. Unless otherwise stated, references to such external documents form that such documents or such sources are prior art with arbitrary authority or form part of common general knowledge in the art. Should not be interpreted as approval.

式（Ｉ）中、
Ｒ₂、Ｒ₃、Ｒ₄およびＲ₅はそれぞれ独立してＨまたはアセチル（ＣＨ₃ＣＯ－）であり、
Ｒ₆はＨまたはＣＨ₃であり、Ｒ₇はＣＨ₃またはＣ2～Ｃ6の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して3～14の整数であり、
但し、Ｒ₆がＨである場合にはｘ＋ｙは10超且つ18以下であり、Ｒ₆がＣＨ₃である場合にはｘ＋ｙは9超且つ17以下である、
方法。
[本発明1002]
式（Ｉ）の化合物の治療上有効な量を含み、

式（Ｉ）中、
Ｒ₂、Ｒ₃、Ｒ₄およびＲ₅はそれぞれ独立してＨまたはアセチル（ＣＨ₃ＣＯ－）であり、
Ｒ₆はＨまたはＣＨ₃であり、Ｒ₇はＣＨ₃またはＣ2～Ｃ6の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して3～14の整数であり、
但し、Ｒ₆がＨである場合にはｘ＋ｙは10超且つ18以下であり、Ｒ₆がＣＨ₃である場合にはｘ＋ｙは9超且つ17以下である、
薬学的組成物。
[本発明1003]
Ｒ₆がＨである、本発明1002の組成物。
[本発明1004]
Ｒ₆がＣＨ₃である、本発明1002の組成物。
[本発明1005]
上皮癌の処置または予防での使用のために、
（ａ）3，8－ジヒドロキシエイコサン酸、
（ｂ）1－（3，8－ジヒドロキシエイコサノイル）グリセロール、
（ｃ）1－（3，8－ジヒドロキシエイコサノイル）2－アセトキシグリセロール、
（ｄ）1－（3，8－ジヒドロキシエイコサノイル）3－アセトキシグリセロール、
（ｅ）1－（3，8－ジヒドロキシエイコサノイル）2，3－ジアセトキシグリセロール、
（ｆ）1－（3，8－ジアセトキシエイコサノイル）2，3－ジアセトキシグリセロール、
（ｇ）3，8－ジヒドロキシエイコサン酸メチルエステル、
（ｈ）3，8－ジヒドロキシヘンエイコサン酸、
（ｉ）1－（3，8－ジヒドロキシヘンエイコサノイル）グリセロール、
（ｊ）1－（3，8－ジヒドロキシヘンエイコサノイル）2－アセトキシグリセロール、
（ｋ）1－（3，8－ジヒドロキシヘンエイコサノイル）3－アセトキシグリセロール、
（ｌ）1－（3，8－ジヒドロキシヘンエイコサノイル）2，3－ジアセトキシグリセロール、
（ｍ）1－（3，8－ジアセトキシヘンエイコサノイル）2，3－ジアセトキシグリセロール、
（ｎ）3，8－ジヒドロキシヘンエイコサン酸メチルエステル、
（ｏ）3，8－ジヒドロキシドコサン酸、
（ｐ）1－（3，8－ジヒドロキシドコサノイル）グリセロール、
（ｑ）1－（3，8－ジヒドロキシドコサノイル）2－アセトキシグリセロール、
（ｒ）1－（3，8－ジヒドロキシドコサノイル）3－アセトキシグリセロール、
（ｓ）1－（3，8－ジヒドロキシドコサノイル）2，3－ジアセトキシグリセロール、
（ｔ）1－（3，8－ジアセトキシドコサノイル）2，3－ジアセトキシグリセロール
および
（ｕ）3，8－ジヒドロキシドコサン酸メチルエステル
または
（ａ）～（ｕ）のいずれか1つの薬学的に許容される塩もしくは溶媒和物
のいずれか1つまたは複数から選択される少なくとも1種の化合物
の治療上有効な量を含む、本発明1002または1003の薬学的組成物。
[本発明1006]
式（Ｉ）の化合物の使用であって、

式（Ｉ）中、
Ｒ₂、Ｒ₃、Ｒ₄およびＲ₅はそれぞれ独立してＨまたはアセチル（ＣＨ₃ＣＯ－）であり、
Ｒ₆はＨまたはＣＨ₃であり、Ｒ₇はＣＨ₃またはＣ2～Ｃ6の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して3～14の整数であり、
但し、Ｒ₆がＨである場合にはｘ＋ｙは10超且つ18以下であり、Ｒ₆がＣＨ₃である場合にはｘ＋ｙは9超且つ17以下であり、
対象の上皮腫瘍形成の阻害、上皮腫瘍成長の阻害、上皮腫瘍転移の阻害または上皮癌の処置もしくは予防での；対象の1種または複数種の腫瘍性上皮細胞のアポトーシスの誘発での；上皮癌治療に対する対象の応答性の増加での；対象の上皮腫瘍の、上皮癌治療に対する感度の増加での；処置に対して耐性を示す、対象の1種または複数種の上皮癌細胞の感受性を高めることでの；上皮癌に罹患している対象の腫瘍性細胞の、上皮癌治療に対する耐性の少なくとも部分的な反転での；上皮癌に苦しめられている患者の、上皮癌治療に対する耐性の完全なもしくは部分的な反転での；あるいは上皮癌治療による処置に対して耐性を示すか、または耐性を示すもしくは耐性を示すようになると予想される、上皮癌に苦しめられている患者の1種または複数種の腫瘍の、上皮癌治療による処置に対する感受性を高めることでの使用のための組成物の製造における、使用。
[本発明1007]
前記対象がヒト対象である、本発明1006の使用。
[本発明1008]
前記化合物が、本発明1002、1003または1004のいずれかで定義された化合物である、本発明1006または1007の使用。
[本発明1009]
（ａ）3，8－ジヒドロキシエイコサン酸、
（ｂ）1－（3，8－ジヒドロキシエイコサノイル）グリセロール、
（ｃ）1－（3，8－ジヒドロキシエイコサノイル）2－アセトキシグリセロール、
（ｄ）1－（3，8－ジヒドロキシエイコサノイル）3－アセトキシグリセロール、
（ｅ）1－（3，8－ジヒドロキシエイコサノイル）2，3－ジアセトキシグリセロール、
（ｆ）1－（3，8－ジアセトキシエイコサノイル）2，3－ジアセトキシグリセロール、
（ｇ）3，8－ジヒドロキシエイコサン酸メチルエステル、
（ｈ）3，8－ジヒドロキシヘンエイコサン酸、
（ｉ）1－（3，8－ジヒドロキシヘンエイコサノイル）グリセロール、
（ｊ）1－（3，8－ジヒドロキシヘンエイコサノイル）2－アセトキシグリセロール、
（ｋ）1－（3，8－ジヒドロキシヘンエイコサノイル）3－アセトキシグリセロール、
（ｌ）1－（3，8－ジヒドロキシヘンエイコサノイル）2，3－ジアセトキシグリセロール、
（ｍ）1－（3，8－ジアセトキシヘンエイコサノイル）2，3－ジアセトキシグリセロール、
（ｎ）3，8－ジヒドロキシヘンエイコサン酸メチルエステル、
（ｏ）3，8－ジヒドロキシドコサン酸、
（ｐ）1－（3，8－ジヒドロキシドコサノイル）グリセロール、
（ｑ）1－（3，8－ジヒドロキシドコサノイル）2－アセトキシグリセロール、
（ｒ）1－（3，8－ジヒドロキシドコサノイル）3－アセトキシグリセロール、
（ｓ）1－（3，8－ジヒドロキシドコサノイル）2，3－ジアセトキシグリセロール、
（ｔ）1－（3，8－ジアセトキシドコサノイル）2，3－ジアセトキシグリセロール
および
（ｕ）3，8－ジヒドロキシドコサン酸メチルエステル
または
（ａ）～（ｕ）のいずれか1つの薬学的に許容される塩もしくは溶媒和物
からなる群のいずれか1種または複数種から選択される少なくとも1種の化合物の使用であって、任意で少なくとも1種の追加の治療剤と併用され、
対象の上皮腫瘍形成の阻害、上皮腫瘍成長の阻害、上皮腫瘍転移の阻害または上皮癌の処置もしくは予防での；対象の1種または複数種の腫瘍性上皮細胞のアポトーシスの誘発での；上皮癌治療に対する対象の応答性の増加での；対象の上皮腫瘍の、上皮癌治療に対する感度の増加での；処置に対して耐性を示す、対象の1種または複数種の上皮癌細胞の感受性を高めることでの；上皮癌に罹患している対象の腫瘍性細胞の、上皮癌治療に対する耐性の少なくとも部分的な反転での；上皮癌に苦しめられている患者の、上皮癌治療に対する耐性の完全なもしくは部分的な反転での；あるいは上皮癌治療による処置に対して耐性を示すか、または耐性を示すもしくは耐性を示すようになると予想される、上皮癌に苦しめられている患者の1種または複数種の腫瘍の、上皮癌治療による処置に対する感受性を高めることでの使用のための組成物の製造における、使用。
[本発明1010]
ヒト対象の上皮腫瘍形成の阻害、上皮腫瘍成長の阻害、上皮腫瘍転移の阻害または上皮癌の処置もしくは予防での；ヒト対象の1種または複数種の腫瘍性上皮細胞のアポトーシスの誘発での；上皮癌治療に対するヒト対象の応答性の増加での；ヒト対象の上皮腫瘍の、上皮癌治療に対する感度の増加での；処置に対して耐性を示す、ヒト対象の1種または複数種の上皮癌細胞の感受性を高めることでの；上皮癌に罹患しているヒト対象の腫瘍性細胞の、上皮癌治療に対する耐性の少なくとも部分的な反転での；上皮癌に苦しめられているヒト患者の、上皮癌治療に対する耐性の完全なもしくは部分的な反転での；あるいは上皮癌治療による処置に対して耐性を示すか、または耐性を示すもしくは耐性を示すようになると予想される、上皮癌に苦しめられているヒト患者の1種または複数種の腫瘍の、上皮癌治療による処置に対する感受性を高めることでの使用のための、本発明1002～1005のいずれかの組成物。
[本発明1011]
上皮癌の処置または予防での使用のための、本発明1010の組成物。
[本発明1012]
プロポリスもしくはポプラまたはその抽出物もしくは滲出物から式（Ｉ）の化合物または式（Ｉ）の化合物の混合物を単離するまたは精製する方法であって、
（ａ）ポプラ抽出物、ポプラ由来プロポリスまたはそれらの抽出物もしくは滲出物を準備する工程、および
（ｂ）該ポプラ、プロポリスまたはそれらの抽出物もしくは滲出物から該化合物を単離するまたは精製する工程
を含む、方法。
[本発明1013]
前記ポプラ抽出物、ポプラ由来プロポリスまたはそれらの抽出物もしくは滲出物が、ポプルス・デルトイデス（Ｐｏｐｕｌｕｓ ｄｅｌｔｏｉｄｅｓ）、その栽培品種、交雑種および雑種を含む、ポプルス・デルトイデスｘニグラ（ｎｉｇｒａ）またはポプルス・エウラメリカナ・ギニエ（Ｐｏｐｕｌｕｓ ｅｕｒａｍｅｒｉｃａｎａ Ｇｕｉｎｉｅｒ）を含むポプルス・デルトイデスの雑種に由来する、本発明1012の方法。
[本発明1014]
前記ポプルス・エウラメリカナ・ギニエが、セルウィン（Ｓｅｌｗｙｎ）、タスマン（Ｔａｓｍａｎ）、ルイサ・アバンゾ（Ｌｕｉｓａ Ａｖａｎｚｏ）およびフレザー（Ｆｒａｓｅｒ）の群から選択される栽培品種である、本発明1013の方法。
[本発明1015]
（ａ）前記ポプラ、プロポリスまたはそれらの抽出物もしくは滲出物を、クロマトグラフィー、例えばカラムクロマトグラフィー、逆相クロマトグラフィー、順相クロマトグラフィーもしくは超臨界液体クロマトグラフィー、および／または溶媒分割、および／または超臨界抽出により分画して、式（Ｉ）の化合物のうちの1種または複数種を含む1つまたは複数の画分を得る工程、
（ｂ）前記ポプラ、プロポリスまたはそれらの抽出物もしくは滲出物または1つまたは複数の画分を、分取ＨＰＬＣおよび／またはポリマー樹脂分画により分画して、式（Ｉ）の化合物のうちの1種または複数種を含む1つまたは複数の画分を得る工程、ならびに任意で
（ｃ）工程（ｂ）の1つまたは複数の画分から式（Ｉ）の1種または複数種の化合物をさらに精製する工程、および／または工程（ｃ）の1つまたは複数の画分から式（Ｉ）の1種または複数種の化合物をさらに精製する工程
のうちの1つまたは複数を含む、本発明1012～1014のいずれかの方法。
[本発明1016]
式（Ｉ）の1種または複数種の化合物を含む組成物または製品であって、式（Ｉ）の1種または複数種の化合物の量および／または濃度が、該組成物または製品と関連する表示上に明記されている、組成物または製品。 The present invention is present in said part, element or feature individually or in combination in any or all combinations of two or more of the parts, elements and features referred to or indicated herein. It can also be broadly stated that if certain integers having equivalents known in the art to which the invention relates are referred to herein, are such known equivalents listed individually? As incorporated herein.
[Invention 1001]
A method of treating or preventing a subject's epithelial cancer, or a method of inducing apoptosis of one or more neoplastic epithelial cells of the subject, in the subject of formula (I) 1 Including the step of administering an effective amount of a species or compound or a pharmaceutically acceptable salt or solvate thereof.

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Method.
[Invention 1002]
Containing therapeutically effective amounts of the compound of formula (I),

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Pharmaceutical composition.
[Invention 1003]
The composition of the present invention 1002, wherein R ₆ is H.
[Invention 1004]
The composition of the present invention 1002, wherein R ₆ is CH ₃ .
[Invention 1005]
For use in the treatment or prevention of epithelial cancer,
(A) 3,8-Dihydroxyeicosanoic acid,
(B) 1- (3,8-dihydroxyeicosanoyl) glycerol,
(C) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
(D) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
(E) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
(F) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
(G) 3,8-Dihydroxyeicosanoic acid methyl ester,
(H) 3,8-dihydroxyheneicosanoic acid,
(I) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
(J) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
(K) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
(L) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
(M) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
(N) 3,8-Dihydroxyheneicosanoic acid methyl ester,
(O) 3,8-dihydroxydokosanoic acid,
(P) 1- (3,8-dihydroxydocosanoyl) glycerol,
(Q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
(R) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
(S) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
(T) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and (u) 3,8-dihydroxydokosanoic acid methyl ester or any one of (a)-(u) pharmaceuticals. The pharmaceutical composition of the present invention 1002 or 1003 comprising a therapeutically effective amount of at least one compound selected from any one or more of a pharmaceutically acceptable salt or solvate.
[Invention 1006]
The use of the compound of formula (I),

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Inhibition of subject epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer; in induction of apoptosis of one or more neoplastic epithelial cells of subject; epithelial cancer Increasing the subject's responsiveness to treatment; in increasing the sensitivity of the subject's epithelial tumor to epithelial cancer treatment; increasing the sensitivity of the subject's one or more epithelial cancer cells that are resistant to treatment By at least a partial reversal of the resistance of the neoplastic cells of the subject suffering from epithelial cancer to the treatment of epithelial cancer; by the complete reversal of the resistance of the patient suffering from the epithelial cancer to the treatment of epithelial cancer. Or in a partial reversal; or one or more patients suffering from epithelial cancer who are or are expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment. Use in the manufacture of compositions for use in increasing the susceptibility of species tumors to treatment with epithelial cancer treatment.
[Invention 1007]
Use of the present invention 1006, wherein the subject is a human subject.
[Invention 1008]
Use of the invention 1006 or 1007, wherein said compound is the compound defined in any of the inventions 1002, 1003 or 1004.
[Invention 1009]
(A) 3,8-Dihydroxyeicosanoic acid,
(B) 1- (3,8-dihydroxyeicosanoyl) glycerol,
(C) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
(D) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
(E) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
(F) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
(G) 3,8-Dihydroxyeicosanoic acid methyl ester,
(H) 3,8-dihydroxyheneicosanoic acid,
(I) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
(J) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
(K) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
(L) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
(M) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
(N) 3,8-Dihydroxyheneicosanoic acid methyl ester,
(O) 3,8-dihydroxydokosanoic acid,
(P) 1- (3,8-dihydroxydocosanoyl) glycerol,
(Q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
(R) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
(S) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
(T) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and (u) 3,8-dihydroxydokosanoic acid methyl ester or any one of (a)-(u) pharmaceuticals. Use of at least one compound selected from any one or more of the group consisting of qualifyingly acceptable salts or solvates, optionally in combination with at least one additional therapeutic agent.
Inhibition of subject epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer; in induction of apoptosis of one or more neoplastic epithelial cells of subject; epithelial cancer Increasing the subject's responsiveness to treatment; in increasing the sensitivity of the subject's epithelial tumor to epithelial cancer treatment; increasing the sensitivity of the subject's one or more epithelial cancer cells that are resistant to treatment By at least a partial reversal of the resistance of the neoplastic cells of the subject suffering from epithelial cancer to the treatment of epithelial cancer; by the complete reversal of the resistance of the patient suffering from the epithelial cancer to the treatment of epithelial cancer. Or in a partial reversal; or one or more patients suffering from epithelial cancer who are or are expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment. Use in the manufacture of compositions for use in increasing the susceptibility of species tumors to treatment with epithelial cancer treatment.
[Invention 1010]
Inhibition of epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer in human subjects; in induction of apoptosis of one or more neoplastic epithelial cells in human subjects; One or more epithelial cancers in human subjects that are resistant to treatment; in increased responsiveness of human subjects to treatment of epithelial cancer; in increased sensitivity of epithelial tumors in human subjects to treatment of epithelial cancer; By increasing the susceptibility of the cells; with at least a partial reversal of the resistance of neoplastic cells of human subjects suffering from epithelial cancer to the treatment of epithelial cancer; the epithelium of human patients suffering from epithelial cancer. Suffering from epithelial cancer, with a complete or partial reversal of resistance to cancer treatment; or with or expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment The composition of any of 1002-1005 of the present invention for use in increasing the susceptibility of one or more tumors of a human patient to treatment with epithelial cancer treatment.
[Invention 1011]
The composition of the present invention 1010 for use in the treatment or prevention of epithelial cancer.
[Invention 1012]
A method of isolating or purifying a compound of formula (I) or a mixture of compounds of formula (I) from propolis or poplar or an extract or exudate thereof.
(A) Preparation of poplar extract, poplar-derived propolis or extracts or exudates thereof, and (b) Isolation or purification of the compound from the poplar, propolis or extracts or exudates thereof. Including methods.
[Invention 1013]
The poplar extract, poplar-derived propolis or extracts or exudates thereof include popls deltoides, their cultivated varieties, hybrids and hybrids, popls deltoides x nigra or popls euramelikana. The method of the present invention 1012, which is derived from a hybrid of Popls del Toides, including Populus euramericana Guinier.
[Invention 1014]
The method of the present invention 1013, wherein the popls Euramericana ginier is a cultivar selected from the group Serwin, Tasman, Luisa Avanza and Fraser.
[Invention 1015]
(A) Chromatography, eg column chromatography, reverse phase chromatography, normal phase chromatography or supercritical liquid chromatography, and / or solvent partitioning, and / or chromatography of the poplar, propolis or extracts or exudates thereof. A step of fractionating by supercritical extraction to obtain one or more fractions comprising one or more of the compounds of formula (I).
(B) The poplar, propolis or an extract or exudate thereof or one or more fractions are fractionated by preparative HPLC and / or polymer resin fraction, among the compounds of formula (I). The step of obtaining one or more fractions comprising one or more, and optionally (c) one or more compounds of formula (I) further from the one or more fractions of step (b). INDUSTRIAL APPLICABILITY, comprising one or more of a step of purifying and / or a step of further purifying one or more compounds of formula (I) from one or more fractions of step (c). One of the 1014 methods.
[Invention 1016]
A composition or product comprising one or more compounds of formula (I), wherein the amount and / or concentration of one or more compounds of formula (I) is associated with the composition or product. The composition or product specified on the label.

Detailed Description The present invention relates to a fatty acid compound having antiepithelial cancer activity and a composition containing the dihydroxy fatty acid glyceride. Pharmaceutical compositions (eg, anti-epithelial cancer compositions) provide and / or enhance anti-epithelial cancer effects, and in certain embodiments, the activity and physics of compositions containing this compound (eg, propolis and propolis extracts). Enhances target characteristics. Functional food compositions (eg, skin and gastrointestinal health compositions) provide health benefits. In certain embodiments, the activity and physicochemical properties of the composition are enhanced, for example in the presence of propolis or propolis extracts or fractions or poplar extracts or fractions.

（式（Ｉ）中、
Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５はそれぞれ独立ししてＨまたはアセチル（ＣＨ_３ＣＯ－）であり、
Ｒ_６はＨまたはＣＨ_３であり、Ｒ_７はＣＨ_３またはＣ２～Ｃ６の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して３～１４の整数であり、
但し、Ｒ_６がＨである場合にはｘ＋ｙは１０超且つ１８以下であり、Ｒ_６がＣＨ_３である場合にはｘ＋ｙは９超且つ１７以下である）
の化合物またはその薬学的に許容される塩もしくは溶媒和物の治療上有効な量を含む組成物の有効な量を投与することを含む方法に関する。 In one aspect, the invention is a method of treating or preventing a subject's epithelial cancer, wherein the subject is in need of formula (I) :.

(In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less).
The present invention relates to a method comprising administering an effective amount of a composition comprising a therapeutically effective amount of a compound thereof or a pharmaceutically acceptable salt or solvate thereof.

ｂ）１－（３，８－ジヒドロキシエイコサノイル）グリセロール、

ｃ）１－（３，８－ジヒドロキシエイコサノイル）２－アセトキシグリセロール、

ｄ）１－（３，８－ジヒドロキシエイコサノイル）３－アセトキシグリセロール、

ｅ）１－（３，８－ジヒドロキシエイコサノイル）２，３－ジアセトキシグリセロール、

ｆ）１－（３，８－ジアセトキシエイコサノイル）２，３－ジアセトキシグリセロール、

ｇ）３，８－ジヒドロキシエイコサン酸メチルエステル、

ｈ）３，８－ジヒドロキシヘンエイコサン酸、

ｉ）１－（３，８－ジヒドロキシヘンエイコサノイル）グリセロール、

ｊ）１－（３，８－ジヒドロキシヘンエイコサノイル）２－アセトキシグリセロール、

ｋ）１－（３，８－ジヒドロキシヘンエイコサノイル）３－アセトキシグリセロール、

ｌ）１－（３，８－ジヒドロキシヘンエイコサノイル）２，３－ジアセトキシグリセロール、

ｍ）１－（３，８－ジアセトキシヘンエイコサノイル）２，３－ジアセトキシグリセロール、

ｎ）３，８－ジヒドロキシヘンエイコサン酸メチルエステル、

ｏ）３，８－ジヒドロキシドコサン酸、

ｐ）１－（３，８－ジヒドロキシドコサノイル）グリセロール、

ｑ）１－（３，８－ジヒドロキシドコサノイル）２－アセトキシグリセロール、

ｒ）１－（３，８－ジヒドロキシドコサノイル）３－アセトキシグリセロール、

ｓ）１－（３，８－ジヒドロキシドコサノイル）２，３－ジアセトキシグリセロール、

ｔ）１－（３，８－ジアセトキシドコサノイル）２，３－ジアセトキシグリセロール、

ｕ）３，８－ジヒドロキシドコサン酸メチルエステル、

または
ａ）～ｕ）のいずれか１つの薬学的に許容される塩もしくは溶媒和物
からなる群のいずれか１つまたは複数から選択される少なくとも１種の化合物の治療上有効な量を含む組成物の有効な量を投与することを含む方法に関する。 In one aspect, x is 4 or more. In one aspect, the invention is a method of treating or preventing a subject's epithelial cancer, the subject in need.
a) 3,8-Dihydroxyeicosanoic acid,

b) 1- (3,8-dihydroxyeicosanoyl) glycerol,

c) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,

d) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,

e) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,

f) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,

g) 3,8-Dihydroxyeicosanoic acid methyl ester,

h) 3,8-dihydroxyheneicosanoic acid,

i) 1- (3,8-dihydroxyheneicosanoyl) glycerol,

j) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,

k) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,

l) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,

m) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,

n) 3,8-Dihydroxyheneicosanoic acid methyl ester,

o) 3,8-dihydroxydocosic acid,

p) 1- (3,8-dihydroxydocosanoyl) glycerol,

q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,

r) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,

s) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,

t) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol,

u) 3,8-Dihydroxydocosanic acid methyl ester,

Or a composition comprising a therapeutically effective amount of at least one compound selected from any one or more of the group consisting of any one of a) to u) pharmaceutically acceptable salts or solvates. It relates to a method comprising administering an effective amount of a substance.

The compound and the pharmaceutical compositions (eg, anticancer compositions) are used in some embodiments to treat or prevent epithelial cancer, or in other embodiments (eg, propolis, extracts of propolis). Alternatively, in fractions, propolis resins, or propolis resin extracts, or embodiments in which poplar extracts or fractions are present), they are used to improve skin health, and / or propolis, propolis extracts or Used to enhance the activity and physicochemical properties of fractions, propolis resins, or propolis resin extracts, or substances containing propolis.

Therefore, on the premise that the anti-epithelial cancer composition is formulated to be suitable for administration to a mammalian subject (for example, this anti-epithelial cancer composition consists of a substance that is safe for the human body). This anti-epithelial cancer composition can be used for the production of anti-epithelial cancer pharmaceutical compositions and drugs, as well as functional food compositions, consumer goods (eg, beverages, foods, lotions, skin creams and the like).

In addition, the long-term maintenance of the anti-epithelial cancer activity of the aspects of the composition described herein can reduce the dose or frequency of administration of the composition, or result in higher efficacy. Or both.

The phrase "anti-epithelial cancer composition" or "composition having anti-epithelial cancer activity" (used interchangeably herein) contemplates compositions of all kinds. As an example, propolis, propolis resin or propolis resin extract and cyclodextrin rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Examples thereof include an anti-epithelial cancer composition containing, or an anti-epithelial cancer composition containing cyclodextrin and a substance containing propolis, a propolis resin or a propolis resin extract. Synergistic compositions (eg, those that enhance any antiepithelial cancer activity observed alone, either propolis or cyclodextrin) are specifically contemplated. In certain embodiments, the anti-epithelial carcinoma composition can be an anti-basal cell carcinoma composition, an anti-squamous cell carcinoma composition or an anti-melanoma composition. In another aspect, the anti-epithelial cancer composition is an anti-gastrointestinal cancer composition (eg, an anti-colorectal cancer composition, an anti-stomach cancer composition or an anti-throat cancer composition).

The term "and / or (and / or)" can mean "and" or "or".

The terms "cancer" and "carcinogenic" refer to a mammalian physiological condition generally characterized by abnormal or disordered cell proliferation, cell survival, cell motility, neoplasmicity and / or carcinogenicity. Cancer and cancer pathology are, for example, metastasis, interference with the normal functioning of adjacent cells, release of cytokines or other secretory products at abnormal levels, suppression or worsening of inflammatory or immune responses, neoplasms, premalignant, It may be associated with malignancy, infiltration of surrounding or distal tissues or organs (eg, lymph nodes), etc. Specifically included are basal cell carcinoma, squamous cell carcinoma, melanoma and precancerous conditions, including dermal tumors, epithelial tumors, buccal oral tumors, such as buccal oral squamous cell carcinoma. , Intraepithelial carcinoma, and invasive basal cell carcinoma, squamous cell carcinoma or melanoma carcinoma, and secondary tumors derived from them. Also particularly included are gastrointestinal cancers (eg colorectal cancer) and precancerous conditions, including epithelial tumors, non-epithelial tumors, carcinomas (eg intraepithelial cancer) and invasive colorectal cancer. Can be included. Also included are gastric and precancerous conditions, which may include epithelial tumors, adenocarcinomas, gastric lymphomas, carcinoid tumors, and stromal tumors. Also included are laryngeal and precancerous conditions, which may include epithelial tumors, squamous cell carcinomas, and adenocarcinomas. Cancer of mucosal tissue is similarly specifically contemplated. The cancer can be, for example, carcinoma in situ and invasive cancer.

The term "comprising", as used herein, means "becomes at least partially". When interpreting a description including this term herein, all features preceded by this term must be present in each description, but other features may also be present. Related terms such as "comprise" and "comprised" should be interpreted in a similar manner.

The "effective amount" is the amount required to impart a therapeutic effect. The interrelationships of doses to animals and humans (based on milligrams per square meter of body surface) have been described by Freireich et al. (1966). Body surface area can be largely determined from the height and weight of the subject. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 1970, 537. Effective doses will also depend on the route of administration, the amount of additives used and the like, as will be appreciated by those of skill in the art.

As used herein, Poplar's "extract" or "fraction" is suitable for use in the present invention, provided that the "extract" or "fraction" is one or more. Contains at least one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof that retain at least the antiepithelial cancer activity of. Exemplary extracts or fractions of poplar for use herein are one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvents thereof. It is rich in Japanese products. Examples of such functional extracts include the anti-epithelial cancer preparations described in the examples herein. Extracts or fractions of poplar rich in one or more of the compounds of formula (I) can be prepared additively or subtractively (thus at least partially isolated or purified). The compound of formula (I) can be added to the composition (eg, an extract or fraction of poplar or poplar) or the extraction of poplar or poplar of a compound other than one or more compounds of formula (I). It will be appreciated that it can be prepared by removal from the object or fraction.

As used herein, the "extract" or "fraction" of propolis is suitable for use in the present invention, where this "extract" or "fraction" is indicated by propolis 1 A pharmaceutically acceptable salt or solvate of one or more compounds of formula (I) or one or more thereof that retains at least the activity or potency of the species or multiple antiepithelial cancers. including. Exemplary extracts or fractions of propolis for use herein are one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvents thereof. It is rich in Japanese products. Examples of such functional extracts include the anti-epithelial cancer tincture described in the examples herein. Extracts or fractions of propolis rich in one or more of the compounds of formula (I) can be prepared additively or incrementally (thus at least partially isolated or purified). The compound of formula (I) can be added to the composition (eg, propolis or propolis extract or fraction)) or propolis or propolis extraction of a compound other than one or more compounds of formula (I). It will be recognized that it can be prepared by removal from the object or fraction.

As used herein, chromatography contacts a solid phase with a compound dissolved or dispersed in a solvent phase or otherwise transported, whereby this solid phase is one of the compounds. Refers to a separation process in which a species or plural is selectively delayed compared to other compounds present in the solvent, thereby separation can occur. Examples of types of chromatography processes include column chromatography, liquid chromatography, gas chromatography, supercritical chromatography, size exclusion chromatography, preparative chromatography, solid phase extraction. Chromatographic processes can be used to determine the concentration of a compound in a mixture, to identify unknown compounds, and / or to use as an analytical standard, eg, to obtain detailed structural analysis data. Alternatively, one or more compounds may be isolated for bioassay.

One or more of the compounds or compositions described herein (eg, a composition comprising one or more compounds of formula (I) optionally with propolis or poplar extract). Methods and assays for determining the biological effect of one or more evoked by are well known in the art and examples are described herein using such methods and assays. Efficacy (eg, efficacy of one or more of one or more of the compounds or compositions described herein) can be identified or confirmed, and the compound or composition can be identified. As a substance, one or more functional extracts or functions of Propolis rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Examples include compositions containing a sex fraction (eg, a propolis, a propolis extract, a poplar extract, or a propolis or poplar fraction). For example, one or more of the compounds or compositions described herein, one or more of the carcinogenic traits in a cell (eg, described in the examples herein). Assays for the ability to increase (the) are used to confirm the efficacy of one or more of the compounds or compositions described herein or the functionality of one or more of Propolis or Poplar. Suitable for identifying extracts or functional fractions.

As used herein, "propolis" contemplates propolis produced by honeybees from any plant source. In one aspect, this propolis is a "poplar-derived" propolis. "Poplar-derived" propolis is also known by various names such as "poplar" propolis. For example, this propolis is mainly derived from poplars of one or more species and, to a lesser extent, exudates of birch, larch or willow buds and leaves. Propolis is classified into seven major classes based on the plant sources that give rise to the characteristic compounds present (Sforcin and Bankova, 2011. Propolis: is there a potential for the develop of new drugs? 133: 253-260.). These classes are: European, North American, Southern South American, New Zealand "poplar" with high levels of aglycon flavonoids such as chrysin and galangin; plenylated p-cumal such as artepirin C. "Brazilian green" containing acid; rich in aglycon flavonoids such as apigenin, ramnocitrin and kenferid, Russian "kabanoki"; containing polyprenylated benzophenone such as nemoroson and xanthochymol, from Cuba "Red Propolis" from Brazil, Mexico, Venezuelan Chrysin species; Diterpen-rich, Greek, Sicilian, Cretan, Malta " "Mediterranean"; as well as "Pacific" from Okinawa, Taiwan, and Indonesia, including "Propolis".

（式（Ｉ）中、
Ｒ_２、Ｒ_３、Ｒ_４およびＲ_５はそれぞれ独立ししてＨまたはアセチル（ＣＨ_３ＣＯ－）であり、
Ｒ_６はＨまたはＣＨ_３であり、Ｒ_７はＣＨ_３またはＣ２～Ｃ６の飽和のもしくは不飽和の炭化水素であり、
ｘおよびｙはそれぞれ独立して３～１４の整数であり、
但し、Ｒ_６がＨである場合にはｘ＋ｙは１０超且つ１８以下であり、Ｒ_６がＣＨ_３である場合にはｘ＋ｙは９超且つ１７以下である）の構造を有する。 Identification and confirmation of anti-cancer components present in propolis resin is difficult due to the complex and multi-component nature of this propolis resin. "Poplar" propolis resins have also been found to contain many types of compounds, such as sugars, glycerol, simple fatty acids, volatile oils, and glycerol esters of phenolic acids. A previously unreported group of compounds in propolis with previously unknown anti-cancer activity is described herein. These compounds are long chain fatty acids and their equivalent glycerides. In addition, these dihydroxy free fatty acids and glycerides may be partially or completely acetylated. These compounds have the formula (I) :.

(In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less).

As will be appreciated by those of skill in the art, the identity of the propolis and, in some cases, its suitability for a particular use (eg, use in the present invention) can be determined by analysis of the composition of this propolis. The presence and amount of certain compounds, often referred to as "marker compounds" (eg, the compounds discussed herein), are derived from a particular source of propolis (eg, poplar) compared to Brazilian propolis for a particular use. Propolis) makes it possible to determine suitability. In certain aspects of the invention, the presence or amount of one or more marker compounds is determined or assayed prior to formulation of the composition, eg, as a preliminary classification step. In other embodiments, the presence or amount of one or more marker compounds is determined and recorded, for example, on the label associated with the compositions described herein (eg, as an indicator of efficacy or activity). To.

"Indication" may be in any form, including, but not limited to, labels incorporated into the Product, such as labels etched or printed on the surface of the Product or Composition. , For example, printed or etched labels on capsules or tablets, packages or labels associated with this product, such as labels attached to or incorporated into packages containing this product or this composition, this product or Separate material (eg, Certificate of Analysis) provided with the Composition; websites, booklets, brochures or displays related to the sale or marketing of the Product or the Composition.

The compounds of formula (I) can be isolated and / or purified from poplar-derived propolis using methods known in the art. An exemplary method is shown herein. Similarly, compounds of formula (I) can be isolated and / or purified from plant sources (eg, poplars and poplar extracts or exudates) again using methods known in the art. Exemplary methods are also shown herein. The method also comprises one or more compounds of formula (I) present in the compositions described herein or pharmaceuticals thereof, eg, for the purpose of reporting said concentration or said amount. Also suitable for use in determining the concentration or amount of salt or solvate tolerated.

Alternatively, the compound of formula (I) can be synthetically prepared using methods well known in the art. For example, Grignard reactions using known starting materials (Mith, Michael B .; March, Jerry (2007), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (6th ed.), New York), New York. The synthesis according to -471-72091-7) is specifically contemplated for the synthesis of the compound of formula (I). For example, the compound of formula (I) may be prepared from the starting material 3,8-dihydroxyoctanoic acid and a Grignard reagent selected from dodecylmagnesium bromide, tridecymagnesium bromide or tetradecylmagnesium bromide. Conceivable. These Grignard reagents can be prepared from the corresponding long chain fatty alcohols dodecanol-1-ol (lauryl alcohol), 1-toridecanol or 1-tetradecanol (myristol alcohol). It is further believed that the primary alcohol of 3,8-dihydroxyoctanoic acid will be selectively oxidized to an aldehyde to allow Grignard coupling of the starting material. The resulting 3,8-dihydroxy fatty acid is then esterified with a suitable lipase or esterified by standard chemical esterification with glycerol, glycerol-2-acetate or glycerol 2,3-acetate. Then, the main compound of the formula (I) can be obtained.

When used with respect to the compositions described herein or the components of such compositions, the phrase "enhanced activity" or "enhanced antiepithelial cancer activity" and their grammatical equivalents or Derivatives, when present in the composition, have the same amount or concentration of anti-epithelial cancer agent with the amount or concentration of the agent (eg, isolated agent) in the absence of the composition. Having a high anti-epithelial cancer activity in comparison, and / or the stability of the composition is improved compared to a single component and / or the bioavailability of the composition is a single component. It is intended to mean that it has been improved in comparison. For example, the enhanced activity is at least about 105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190 of the original activity. 195, 200% or higher, the effective range can be selected from between any of these values (eg, about 105 to about 200%, about 120 to about 200%, about 140 to about 200%, about 150 to about). 200%, about 180-about 200% and about 190-about 200%). In certain embodiments, the composition may exhibit enhanced anti-epithelial cancer activity, i.e., at least about 105, 110, 115, 120, 125, 130, 135, 140 of the anti-epithelial cancer activity of propolis alone or cyclodextrin alone. 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200% or higher. Similarly, preferred compositions may support the maintenance of enhanced anti-epithelial cancer activity, ideally enhanced anti-epithelial cancer activity until utilized using the methods contemplated herein. Can be said to hold. This enhanced activity (including enhanced maintenance of activity) is not desired to be bound by any theory, but for example due to the improved water dispersibility among the various components of this composition. It is believed to be the result of synergies or improved stability of this composition or improved bioavailability of this composition.

The term "oral administration" includes oral administration, buccal administration, intestinal administration and gastric administration.

The term "parenteral administration" refers to topical administration (including administration to any dermal, epithelial or mucosal surface), subcutaneous administration, intravenous administration, intraperitoneal administration, intramuscular administration and intratumoral administration (any to the tumor). Including, but not limited to, direct administration).

The term "pharmaceutically acceptable carrier" is intended to refer to carriers including, but not limited to, additives, diluents or auxiliaries that may be administered to a subject as components of the composition. The preferred carrier does not reduce the activity of this composition and is not toxic when administered at a dose sufficient to deliver an effective amount of propolis or an extract thereof, or is otherwise administered. Does not reduce the activity of antiepithelial cancer agents.

The term "(s)" following the noun contemplates the singular, plural, or both.

The term "subject" is intended to refer to an animal (preferably a mammal, more preferably a mammalian companion or human). Preferred companion animals include cats, dogs and horses. Other mammalian subjects include agricultural animals (eg horses, pigs, sheep, goats, cows, deer or poultry) or laboratory animals (eg monkeys, rats or mice).

The term "treat" and its derivatives should be terminated in the broadest possible sense. This term should not be understood to imply that the subject will be treated until full recovery. Therefore, to "treat" is to maintain the progression or symptoms of the subject's disease at a substantially static level, increase the subject's recovery rate, develop or remit the symptoms of a particular condition. And / or prevention, or improving the patient's quality of life is broadly included. The term "treat" also broadly includes the construction of stamina for maintaining good health and preventing disease for sensitive individuals.

Exemplary Uses of the Invention The methods and compositions described herein include epithelial cancers, neoplastic disorders associated with epithelial cells, and symptoms of such cancers (cancer treatment and associated disorders). ) Can be used for treatment or prevention.

In one example, the methods and compositions described herein are used to treat or treat skin cancer (eg, melanoma, neoplastic disorders associated with melanoma, and symptoms of melanoma, melanoma treatment and related disorders). Can be used for prevention. Melanoma (also called malignant melanoma) is a tumor condition that affects melanoma-forming cells.

Melanoma is an uncommon but most aggressive and threatening skin cancer. If possible, the preferred procedure is complete surgical resection, which can be curative in the absence of metastases.

The methods and compositions described herein are used in the treatment or prevention of basal cell carcinoma, neoplastic disorders associated with basal cancer cells, and symptoms of basal cell carcinoma, basal cell carcinoma treatment and related disorders. obtain. Basal cell carcinoma is a tumor condition affected by the basal cells of the dermis.

Basal cell carcinoma originates in the lowest layer of the epidermis. If possible, the preferred procedure is a complete surgical resection that can be curative.

In certain embodiments, the method and the composition are used to treat or prevent squamous cell carcinoma, neoplastic disorders associated with squamous cell carcinoma cells, and squamous cell carcinoma, squamous cell carcinoma treatment and related disorders. Used in.

Squamous epithelial cell carcinoma is a tumor condition that occurs in cells in the middle layer of the epidermis. Although squamous cell carcinoma is less common than basal cell carcinoma, it can be fatal if metastases are more likely and untreated.

The present invention is a method and composition for inhibiting skin tumor formation of a subject in need, inhibiting skin tumor growth, inhibiting skin tumor metastasis, or treating or preventing skin cancer. I will provide a. Although not bound by any theory, Applicants say that inhibition occurs at least partially, for example by preventing UV-induced damage to DNA or by preventing or reducing the formation of reactive oxygen species. think.

In certain aspects, the invention is also a method of at least partially reversing the resistance of a subject tumor cell suffering from skin cancer to skin cancer treatment, or in a patient suffering from skin cancer. , A method of completely or partially reversing resistance to skin cancer treatment, or showing or expected to be resistant to or expected to be resistant to treatment with skin cancer treatment. A method of increasing the susceptibility of one or more tumors of a patient suffering from cancer to the patient with propolis, propolis resin or propolis resin extraction rich in one or more compounds of formula (I). It also relates to a method comprising the step of administering a composition comprising or consisting essentially of the substance and cyclodextrin.

In one aspect, the one or more tumors have increased activation of one or more precancerous cell survival signaling pathways within or within the tumor. Treatment of skin cancer due to increased activation of one or more of the AKT, JNK or JAK / STAT signaling pathways within a sample from a patient (eg, tissue sample, tumor sample or blood or plasma sample). Is resistant to, or is expected to be resistant or resistant to.

Precancerous cell survival signaling pathways involved in the development and development of skin cancer are known in the art.

The method and the composition can be used in the treatment or prevention of melanoma, neoplastic disorders associated with melanoma cells, and symptoms of melanoma, melanoma treatment and related disorders.

The most common treatments are surgical resection of the tumor and radiation therapy. Chemotherapeutic agents may be used in combination with surgery and / or radiation.

The method and the composition can also be used to maintain or improve the health of the skin.

This includes treatment or prevention of conditions associated with unhealthy skin, low immunity and skin inflammation. For example, the method and the composition are useful in the treatment or prevention of or in the treatment or prevention of skin aging, sunburn, dermatitis, eczema, psoriasis, fish scales and related inflammatory conditions, and red skin, inflammation. It is useful in the treatment or prevention of caused skin, dry skin or sensitive skin.

Propolis and substances containing propolis Propolis is generally available in New Zealand and elsewhere as a resinous sticky solid. Propolis can be obtained from honeycombs and the resulting propolis is stored, for example, to assess propolis content. Typically, propolis or its extract is processed into fine particle form or concentrated tincture. Various methods are known for preparing active propolis or its extract into particulate form or concentrated tincture. Most commonly, ethanol or an ethanol / water mixture is used to extract crude propolis to produce a dilute tincture. The wax associated with this crude propolis is largely insoluble in the solvent and therefore most is not extracted. Any wax extracted can be removed by cooling the dilute tincture and then precipitating, filtering or centrifuging. The tincture is then partially concentrated to complete the evaporation of the solvent to give a concentrated tincture, which is then optionally freeze-dried to give a powder. Alternatively, the tincture can be spray dried to obtain a powder. Fractions can be prepared by methods known in the art (eg, chromatography using a size exclusion matrix or reverse phase matrix (eg HPLC), or supercritical fractions). A typical solvent for use in such a chromatographic process is ethanol or another water-miscible alcohol.

In one aspect, the propolis or concentrated propolis tincture is present in other compounds that enhance the properties of propolis (eg, compounds that enhance ease of formulation or administration, or compounds that enhance antiepithelial cancer activity, or in propolis. Combined with one or more compounds that enhance the stability of antiepithelial cancer activity). Examples of additional compounds are those that improve the therapeutic benefits of propolis. Exemplary compositions in which one or more compounds are present in propolis and in poplar-derived propolis (specifically, eg, biologically active compounds such as CAPE, caffeic acid, pinocembrin, benzyl caffeate, Sinnamyl caffeate, benzyl ferulate, cinnamyl ferulate, chrysin, tectochrysin, galangin, pinocembrin, pinocembrin chalcone and pinocembrin-3-acetate) are particularly contemplated. In other examples, additional compounds may be included to improve or maintain the physiological benefits of the composition, for example mannitol may be added to enhance the diuretic properties of the resulting composition. Alternatively, or in addition, the addition of other compounds such as additives and / or sprays may improve the administration, production or delivery properties of the composition.

In a specifically contemplated embodiment, the dewaxed propolis resin, optionally supplemented with one or more additional compounds, is encapsulated with cyclodextrin and the mixture is dried. Further mixing is performed, for example, to obtain a particle size distribution that allows easy mixing with other components of the composition, ease of tableting, or ease of administration to the subject.

In a typical embodiment, the propolis or propolis resin is sterilized by, for example, heating to kill bacteria, protozoans, yeasts, fungi and other organisms that may be naturally present in the propolis.

Poplar Extract As described in the examples herein, the exemplary compound of formula (I) has been identified with an extract prepared from poplar (Populus spp.) And is specific. Has been identified from exudates prepared from shoots, leaf materials and twigs. Without wishing to be bound by any theory, Applicants say that the compounds described herein are present in or related to poplar-derived propolis and propolis resins. think. For use in the present invention, poplar or propolis extracts can be processed into forms suitable for further processing and encapsulation with, for example, cyclodextrin, or extracted with a solvent (eg, alcohol) while preserving the bioactive component. Those skilled in the art will recognize that they will get it. Typically, this propolis or poplar extract is processed into fine particle form or concentrated tincture.

Cyclodextrins and Substances Containing Cyclodextrins Cyclodextrins are cyclic molecules composed of glucopyranose ring units that form toroidal structures. The inside of the cyclodextrin molecule is hydrophobic and the outside is hydrophilic, so that the cyclodextrin molecule becomes water-soluble. Solubility can be altered by substitution of hydroxyl groups on the outside of cyclodextrin. Similarly, the internal hydrophobicity can be altered by substitution, but in general the internal hydrophobicity allows the accommodation of relatively hydrophobic guests within the cavity. Containment of one molecule within another is known as complex formation, and the resulting product is referred to as an inclusion complex. Cyclodextrins are typically identified based on the number of monomeric units that make up this molecule, alpha-cyclodextrins (α-cyclodextrins) contain 6 monomeric units, and beta-cyclodextrins (β-cyclo). Dextrin) contains 7 monomer units and gamma-cyclodextrin (γ-cyclodextrin) contains 8 monomer units. A larger cyclodextrin molecule (eg, a well-characterized cyclodextrin containing 32 1,4-anhydroglucopyranoside units) is described.

The cyclodextrin molecule can be conveniently derivatized, for example by chemical modification, to alter, for example, one or more of the physicochemical properties of the cyclodextrin molecule. Examples of cyclodextrin derivatives include methylated cyclodextrins, sulfobutylcyclodextrins, maltosylcyclodextrins, hydroxypropylcyclodextrins such as beta-hydroxylpropylcyclodextrins and gamma-hydroxypropylcyclodextrins and salts thereof. Those skilled in the art will recognize that various derivatives of cyclodextrin may be suitable for a particular purpose, for example, certain derivatives of cyclodextrin are not acceptable for administration to human subjects but are suitable for industrial applications. ..

The cyclodextrins constituting the anti-epithelial cancer compositions described herein can be commercially available or independently prepared by methods well known to those of skill in the art. Cyclodextrins used in antiepithelial cancer compositions for administration to subjects (eg, cyclodextrins for the manufacture of beverages, foods or pharmaceuticals) should be safe for the human body and are preferably pharmaceutical. It will be clear to those skilled in the art that it is an acceptable cyclodextrin.

In a specifically contemplated embodiment, a combination comprising alpha-cyclodextrin, gamma-cyclodextrin, or alpha-cyclodextrin, gamma-cyclodextrin, or both is used. In such an embodiment, the anti-epithelial cancer activity is substantially enhanced as shown in the examples herein. Such compositions comprising alpha-cyclodextrin and / or gamma-cyclodextrin can be formulated to provide, for example, enhanced texture or palatability, eg, with alpha-cyclodextrin and / or gamma-cyclodextrin. Compositions containing and with propolis show a strong tendency to hide any unpleasant flavor present in this propolis.

Cyclodextrins suitable for use in the present invention can be obtained from commercial sources or can be independently prepared by methods well known in the art (eg, from starch by enzymatic conversion). In certain embodiments, CAVAMAX W6, W7 or W8 FOOD, which are alpha, beta or gamma-cyclodextrins commercially available from Wacker AG, are used.

In certain embodiments (eg, those intended for topical application of the composition), non-food grade cyclodextrins are used, for example cyclodextrins such as substituted cyclodextrins from cyclodextrins in the CAVASOL range are contemplated.

Carcinoma Examples of carcinomas suitable for treatment with the compositions described herein include carcinomas, such as squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, large cell carcinoma, small cell carcinoma and transition. Examples include epithelial carcinoma. It will be understood that carcinoma is a commonly used term for malignant epithelial tumors. There are two major types of carcinoma, which are classified according to the type of epithelium from which the carcinoma is derived. These major types are squamous cell carcinoma derived from squamous epithelium and adenocarcinoma derived from glandular epithelium.

In various embodiments, epithelial cancers are selected from the group including: gastric cancer (intestinal), gastric cancer (diffuse / mucous), moderately differentiated adenocarcinoma of the colon, poorly differentiated adenocarcinoma of the colon (mucous). Sex), hepatocellular carcinoma such as poorly differentiated hepatocellular carcinoma, renal cell carcinoma (Grawitz tumor), endometrial cancer, breast cancer such as invasive breast cancer, metastatic cancer (lymph node), colorectal cancer , Oral cancer (eg esophageal cancer, pharyngeal cancer or laryngeal cancer), skin cancer (eg basal cell skin cancer, squamous epithelial cell skin cancer and melanoma), and ovarian cancer.

Oral or laryngeal cancer (also referred to as esophageal, pharyngeal or laryngeal cancer), and pharynx, nasopharynx, mesopharynx, hypopharynx, laryngeal (also referred to as esopharyngeal, pharyngeal or laryngeal cancer) using the methods and compositions described herein. Treatment of a comprehensive tumor that develops in the tissue of the pharynx) or tonsils is specifically intended. Similarly, treatment of gastric cancer or stomach cancer, basal cell skin cancer, squamous cell skin cancer and melanoma is specifically contemplated.

Composition The exemplary anti-epithelial carcinoma composition is pharmaceutically acceptable of one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. Included with the carrier.

Suitable compositions for administration to subjects are foods, beverages, food additives, beverage additives, nutritional supplements, nutritional products, functional cosmetics, medical foods, functional foods, medical supplies, medical devices, drugs or pharmaceuticals. Can be formulated as. Skilled workers in the art with respect to the techniques and teachings herein may prepare suitable formulations.

To allow administration of the compositions useful herein to a subject by any selected route (eg, oral or parenteral (eg, topical, subcutaneous, intramuscular and intravenous) administration). Can be formulated into. The route of administration to the subject typically takes into account the purpose for which the composition is administered (eg, administering a pharmaceutical composition to improve skin health or treat or prevent skin cancer). It will be appreciated by those skilled in the art that this route of administration is typically chosen taking into account the health aspects of the target or the nature of the skin cancer.

In general, for oral administration, prescribed diets (eg foods, food additives or dietary supplements), functional foods or pharmaceutical compositions useful herein are formulated by skilled workers of known formulation techniques. Can be done. In certain embodiments, the composition formulated for oral administration comprises gamma-cyclodextrin. In certain embodiments, the composition formulated for oral administration comprises alpha-cyclodextrin.

Therefore, a pharmaceutical composition useful according to the present invention can be used as an appropriate pharmaceutically acceptable carrier (eg, additives, diluents, auxiliaries and theirs) selected for the intended route of administration and standard pharmaceutical practice. Can be formulated with (combination). For example, Remington's Pharmaceutical Sciences, 16th edition, Osol, A. et al. Ed. , Mac Publishing Co., Ltd. , 1980.

One suitable route of administration of a particular embodiment (eg, one comprising one or more compounds of formula (I)) is oral, but any composition to any mode of administration (eg, of a different agent). It should be understood that administration by multiple routes, such as different routes for) may be appropriate. Therefore, inhalation of any composition (nasal or oral inhalation) as well as vaginal and rectal administration is also contemplated. Intramedullary, epidural, intraarticular and intrapleural administration of any composition is also contemplated. Optional by the first route of administration with separate, simultaneous or continuous administration of one or more other agents (eg, one or more other anti-epithelial cancer agents) by the second route of administration Also contemplated are administration of the composition with at least one additional anti-epithelial cancer factor (eg, oral administration of the composition with topical administration of at least one additional anti-epithelial cancer agent).

The present composition can also be formulated as a dosage form. Dosage forms useful herein can be orally administered as powders, solutions, tablets or capsules. Suitable dosage forms may contain additional agents (eg, emulsifiers, antioxidants, flavoring agents or colorants) as needed, or may have an enteric coating. Suitable enteric coatings are known. An enteric coating that surrounds the active ingredient, and prevents the release of the active ingredient in the stomach, but allows the release after the dosage form has left the stomach. Dosage forms useful herein may be adapted for immediate release, delayed release, modified release, sustained release, pulsed release or controlled release of the active ingredient. Suitable formulations may include additional agents (eg, emulsifiers, antioxidants, flavoring agents or colorants) as needed.

Capsules may contain any standard pharmaceutically acceptable substance such as gelatin or cellulose. The tablet can be formulated according to conventional procedures by compressing the mixture of active ingredients with a solid carrier and lubricant. Examples of solid carriers include starch and sugar bentonite. The active ingredient may be administered in the form of hard shell tablets or in the form of capsules containing binders (eg lactose or mannitol), conventional excipients and tablet molding agents. The pharmaceutical composition can also be administered by parenteral route. Examples of parenteral dosage forms include aqueous solution, isotonic saline, or active agent 5% glucose, or other known pharmaceutically acceptable additives. Solubilizers known to those of skill in the art can be utilized as pharmaceutical additives for the delivery of anti-epithelial cancer agents.

The dosage form for injection can be formulated as a liquid solution or suspension. Solid forms suitable for liquid solutions or suspensions can also be prepared prior to injection. This dosage form may be emulsified. A carrier (eg, water, saline, dextrose, glycerol, ethanol, or the like) is a compound of one or more of formula (I) or a pharmaceutically acceptable salt or solvate thereof. , And combinations thereof).

Sustained release preparations can be prepared. Suitable examples of sustained release preparations include one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, optionally propolis and / or poplar. Included is a semi-permeable matrix of solid hydrophobic polymers containing an extract and / or cyclodextrin and, if present, at least one additional anti-epithelial cancer agent. This matrix can be in the form of an article (eg, film or microcapsule). Examples of sustained release matrices are polyesters, hydrogels (eg poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohols)), polylactides (see US Pat. No. 3,773,919), L-. Injectable microspheres composed of glutamate and ethyl-L-glutamate copolymers, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT ™ (lactic acid-glycolic acid copolymer and leuprolide acetate). ).

Compositions (eg, one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof, or abundant propolis, propolis resin or propolis extract, and cyclo. Topical formulations containing dextrin and / or those containing at least one additional anti-epithelial cancer agent, if present) are specifically contemplated. Using known carriers for such applications, topical formulations can be prepared as lotions, creams, ointments, pastes or ointments. In certain embodiments, the composition formulated for topical administration comprises alpha, beta or gamma-cyclodextrin.

In certain embodiments, the topical formulation is one or more penetrants (eg, one or more alkyl lactates), one or more antioxidants (eg, vitamin E (alpha-tocopherol) or another). Naturally occurring antioxidants such as polyphenolic antioxidants such as proanthocyanidin and chlorogenic acid, quinic acid and ferulic acid), one or more photoprotectors or UV protectants (eg TiO2 or carnosic acid). Includes one or more lipids, collagens, keratins or other proteins.

In certain embodiments, the topical composition comprises one or more carriers that are common in cosmetics (eg, hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic activators, preservatives, etc. Includes antioxidants, solvents, fragrances, excipients, UV protectants, pigments, odor absorbers or pigments). Typically, the composition comprises an amount customarily used in the art, eg, 0.01% to 20% with respect to the total weight of the composition. Depending on the nature and specific embodiment of the carrier, the carrier may be a lipid layer, an aqueous phase, or one or more phases, vesicles, eg, one or more lipid vesicles, microparticles, or for topical use thereof. Introduced into other components of the formulation.

In certain embodiments, the lipid / fatty phase ratio can range from 5% to 80% by weight, eg, if the composition is an emulsion. It can be in the range of 5% by weight to 50% by weight. The oils, emulsifiers and co-emulsifiers intended for use in this composition in the form of emulsions are selected from those customarily used in the art. If present, emulsifiers and co-emulsifiers are added to the composition in proportions ranging from 0.3% to 30% by weight (eg, 0.5% to 20% by weight) based on the total weight of the composition. exist.

In certain embodiments, the composition comprises one or more oils, eg, one or more mineral oils such as liquid petroleum jelly, plant origin oils such as avocado oil or soybean oil, animal origin oils. , For example lanolin, synthetic oils such as perhydrosqualene, silicone oils such as cyclomethicone, and fluoro oils such as perfluoropolyether. In certain embodiments, fatty alcohols (eg, cetyl alcohols), fatty acids and waxes (eg, carnauba wax or zokerite) are also used as fatty substances.

In certain embodiments, the emulsifier and co-emerizer are a fatty acid ester of polyethylene glycol (eg, PEG stearate) or a fatty acid ester of glycerol (eg, glyceryl stearate) or a mixture thereof.

The use of hydrophilic gelling agents is intended for certain formulations, such as carboxyvinyl polymers (eg carbomer), acrylic copolymers (eg acrylate / alkyl acrylate copolymers), polyacrylamides, polysaccharides, natural gums and natural clays. Examples of the lipophilic gelling agent include modified clays such as bentonite, metal salts of fatty acids, hydrophobic silica and polyethylene.

In certain embodiments, representative examples of commercially available base creams for use as pharmaceutically acceptable carriers are Dermabase creams, Unibase creams and Vanicreams.

The present topical preparation also includes, in certain embodiments, a moisturizer, a depigmenting or coloring agent, an antibacterial agent, or a free radical scavenger.

In certain embodiments, the topical composition is formulated as an aqueous formulation, eg, as an aqueous skin cream (eg, a water-in-oil or oil-in-water emulsion).

Such formulations can be administered directly, for example can be applied directly to the wound, sprayed onto the surgical site, or indirectly applied by impregnation into bandages or traumatic pharmaceutical materials, or surgical instruments, traumatic medications. Can be sprayed on materials and the like.

Also parenteral unit dosage forms comprising one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof optionally with at least one additional therapeutic agent. Provided.

In one example, the antiepithelial cancer composition comprises a propolis tincture (eg, one or more of the compounds of formula (I) or a pharmaceutically acceptable salt or solvent-rich propolis tincture thereof). Cyclodextrin and one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof are mixed, then water is added to make this composition. A powder obtained after homogenization and then spray drying or freeze drying. Other exemplary anti-epithelial cancer compositions of the invention include solutions, such as: propolis tincture or a fraction thereof mixed with cyclodextrin and then dispersed in water, propolis or propolis. The substance containing the above and cyclodextrin are independently dissolved or dispersed in water and then mixed, for example by kneading, and the powder or resin of Propolis is further mixed with another organic solvent in which the powder or resin is soluble. Alternatively, it is first dissolved in an organic solvent-water mixture (eg, ethanol, propylene glycol, ethyl acetate, isopropyl alcohol and a mixture thereof with water), the resulting solution is mixed with cyclodextrin and then added to water. And then mixed, for example by kneading, and then dried by means known in the art (eg, spraying or freeze-drying). Alternatively, water can be mixed with cyclodextrin below the solubility of cyclodextrin in water, then propolis tincture, then water is added and mixed, and the resulting dispersion is a means known in the art. Dry by (eg spray or freeze-dry). In certain embodiments, the anti-epithelial cancer composition prepared as the powder described above, for example, the anti-epithelial cancer composition is a solution of the anti-epithelial cancer composition prepared as described above. It may be preferable because it can maintain strong anti-epithelial cancer activity or can maintain anti-epithelial cancer activity for a long period of time.

The content of at least one compound of the formula (I) of the present invention and a cyclodextrin-rich propolis, propolis resin or propolis resin extract is at any level as long as the expected antiepithelial cancer activity is achieved. obtain. Similarly, the content of the compound of formula (I) of the invention, propolis, propolis resin or propolis resin extract and cyclodextrin can be at any level as long as the expected antiepithelial cancer activity is achieved. ..

Without wishing to be bound by any theory, Applicants use propolis, propolis resin or propolis resin extract rich in at least one compound of formula (I) in the composition as said propolis, propolis. It is believed that if the molar ratio of resin or propolis resin extract: cyclodextrin is 1: 1 or less, it will be completely encapsulated.

In some embodiments, the molar ratio of propolis, propolis resin or propolis resin extract: cyclodextrin rich in at least one compound of formula (I) can exceed 1: 1 in the composition. In such compositions, excess propolis, propolis resin or propolis resin extract will not be encapsulated with cyclodextrin.

Other commonly known anti-epithelial cancer substances may be combined with the composition, depending on the application to which the epithelial cancer composition is applied.

Without wishing to be bound by any theory, Applicants apply to one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. The enhanced anti-epithelial cancer activity observed in the exemplary compositions of the invention comprising cyclodextrins is pharmaceutically acceptable of one or more compounds of this formula (I) or one or more thereof. It is believed that the resulting salt or solvate (especially when present as a propolis resin or a concentrated fraction of the propolis resin) may be at least partially due to the synergistic effect between the cyclodextrin. In certain embodiments, the exemplary composition exhibiting synergistic action is one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof (eg, formula). Extracts or fractions of propolis, propolis resin extracts, or poplar extracts rich in one or more compounds of (I) or one or more pharmaceutically acceptable salts or solvates thereof. Alternatively, it is a composition containing an exudate) and alpha-cyclodextrin. In another exemplary embodiment, the synergistic composition is a compound of one or more of formula (I) or a pharmaceutically acceptable salt or solvate thereof (eg, one or more of them). Extraction or Fraction of Propolis Extract or Fraction, Propolis Resin Extract, or Poplar Rich in One or Multiple Compounds of Formula (I) or One or Multiple Pharmaceutically Acceptable Salts or Solvents thereof A composition containing a substance or an exudate) and gamma-cyclodextrin.

In one aspect, the invention relates to the manufacture of foods, beverages, food additives, beverage additives, nutritional supplements, nutritional products, medical foods, functional foods, functional cosmetics, medical devices, medical supplies, drugs or pharmaceuticals. , Propolis, propolis resin or propolis resin extract and cyclodextrin rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or admixtures thereof (eg,). With respect to the use of propolis and optionally at least one antiepithelial cancer agent (alpha-cyclodextrin and / or gamma-cyclodextrin).

In one aspect, an exemplary composition comprising propolis, propolis resin, propolis resin extract, poplar extract or cyclodextrin is formulated for oral administration. In another aspect, the composition is formulated for parenteral (eg, topical) administration. In certain embodiments, the composition comprises inducing apoptosis, treating or preventing skin cancer, maintaining or ameliorating skin health, or the one or more described above. For other uses.

In one aspect, the composition is in the form of a powder, tablet, caplet, pill, hard or soft capsule, or lozenge.

In one aspect, the composition may be a sachet, a distributable powder, a granule, a suspension, an elixir, a liquid, a beverage form, or any other that may be added to a food or beverage such as water or fruit juice. Is in the form of. In one aspect, the composition is an enteral product, a solid enteral product or a liquid enteral product.

In one aspect, the composition is in the form of a cream, ointment, paste, drip solution (eg, eye drops or ear drops), inhalant or inhalable composition, traumatic medicinal material, pad or spray. Is.

In one aspect, the composition further comprises one or more components (eg, antioxidants) that prevent or reduce the decomposition of the composition during or after storage.

In one aspect, useful compositions herein include any edible consumer product, particularly one capable of carrying one or more cyclodextrins. If the composition comprises a proteinaceous factor as at least one additional anti-epithelial cancer agent, the edible consumer product may carry the protein. Examples of suitable edible consumer products are baked foods, powders, liquids, confectionery products, reconstituted fruit products, snack bars, food bars, muse revers, spreads, sauces, dips, dairy products (eg ice cream, yogurt and Cheese), beverages (eg dairy-based and non-dairy-based beverages (eg, dairy and yogurt beverages such as milk shakes), powdered milk, sports supplements or nutritional supplements (eg, dairy-based and non-dairy products) Base sports supplements or honorary supplements), food additives (eg protein sprays), as well as nutritional supplement products (eg nutritional supplement tablets). Within this embodiment, the compositions useful herein are. It can also be a powdered or liquid form of infant-prepared milk powder. Suitable functional food compositions useful herein may be provided in a similar form. Specifically contemplated are milk. Or any fraction of one or more dairy products, or milk components (eg, milk protein, milk protein, initial milk, milk fat), or milk or one or more dairy products or milk components. A composition further comprising (eg, a milk fat fraction, a milk protein fraction, a milky protein fraction, a primary milk fraction or the like).

Compositions useful herein include other elements such as calcium, zinc, magnesium, selenium, vitamin C, vitamin D, vitamin E, vitamin K2, complex carbohydrates, cooking oils or cooking oils such as palms, olives. Soybeans, canolas, corn, sunflowers, benivana, peanuts, grape seeds, sesame seeds, nuts, almonds, cashews, hazelnuts, macadamia, pecans, pistachios and walnuts, as well as other edible products such as acai oil, amaranth oil, apricot oil, argan. Oil, butterfly oil, avocado oil, babas oil, legume oil, cassis seed oil, rurigisa seed oil, Borneo tallow nut oil, yugao oil, buffalo gourd oil, carobpod (algaroba) oil, kofune oil, coendro seed oil, pine yoigusa Oil, Amanazuna oil, Asa oil, Capoc seed oil, Laremantia oil, Meadowfoam seed oil, Karasina oil, Okla seed (hibiscus seed) oil, Perilla seed oil, Peky oil, Pine nut oil, Poppy grain oil, Prune kernel oil , Pumpkin seed oil, quinoa oil, ramtil oil, rice bran oil, chanoki oil, thistle oil, watermelon seed oil or wheat germ oil, or a combination thereof.

In various embodiments, the composition may comprise at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is: an antibiotic such as an aminoglycoside such as ampicillin, gentamycin, canamycin, neomycin, netylmycin. , Streptomycin, tobramycin or paromomycin; ansamycin, eg geldanamycin or harbimycin; carbasephem, eg lorakalvev; carbapenems, eg ertapenem, dripenem, imipenem / silastatin or melopenem; cephalosporins (1st generation), eg cephalosporins, cephalosporins. , Cephalosporins or cephalexins, or cephalexins; cephalosporins (2nd generation), such as cephalosporins, cefamandols, cephoxtin, cefprodil or cefuroxime; cephalosporins (3rd generation), such as cephyxim, cefdinyl, cefdithren, cephoperazone, cefotaxim, Cephalosporins (4th generation); cephalosporins; cephalosporins (5th generation), eg ceftobiplol; glycopeptides such as teicoplanin or bancomycin; macrolides, eg Azithromycin, Clarislomycin, Dirislomycin, Erythromycin, Loxythromycin, Trolleanandmycin, Terrislomycin or Spectinomycin; Xacillin, mezlocillin, methicillin, naphthylin, oxacillin, penicillin, piperacillin or ticarcillin; polypeptides such as basitrasin, erythromycin or polymixin b; quinolones such as cyprofloxacin, enoxacin, gatifloxacin, levofloxacin, romefloxacin, moxyfloxacin. , Norfloxacin or ofloxacin; -Sulfame Toxazole (cotrimoxazole) (tmp-smx); tetracycline, such as demecrocycline, doxicycline, minocycline, oxytetracycline, tetracycline; others, such as arsphenamine, chloramphenicol, clindamycin, lincomicin, Etambutol, phosphomycin, fusidic acid, linezolid, isoniazide, linezolid, metronidazole, mupyrosine, nitrofrantoin, platensimycin, pyrazinamide, quinupristin / dalhopristin, rifampicin (rifampicin in the US), thianphenicol, thianphenicol, tinidazole, dapson, chloramphenicol; Lipopeptides such as daptomycin, glycylcycline, such as tetracycline, or oxazolidinone, such as linezolid.

In other embodiments, the at least one additional therapeutic agent is: an antifungal agent such as a polyene antifungal agent such as natamycin, limosidedin, Philippines, nystatin, anhotericin B, candicine; imidazole such as miconazole, ketoconazole, clotrimazole. Trimazole, econazole, bihonazole, butconazole, fenticonazole, isoconazole, oxyconazole, sertaconazole, sulconazole or thioconazole; triazoles such as fluconazole, itraconazole, isabconazole, loveconazole, posaconazole, boriconazole or terconazole; ); Allylamines such as terbinafine, amorolphin, naphthifin or butenafin; equinocandins such as anidurafungin, caspopofangin or mikafangin; others such as benzoic acid, cyclopyrox, tornafutate, undecylenic acid, flucitosine or 5-fluorocytosine, griseofulvin. , Haloprosin and sodium bicarbonate; or alternatives such as alicin, tea tree oil, citronellasaw oil, iodine, lemongrass, olive leaf, orange oil, palmarosa oil, patchouli, lemon myrtle, neem seed oil, coconut oil, zinc or selenium. Alternatively, the agent is selected from any of those described herein.

The efficacy of compositions useful in accordance with the present invention can be assessed both in vitro and in vivo. See, for example, the examples below. Briefly, in one aspect, the composition can be tested, for example, for its ability to inhibit tumor cell proliferation in vitro. For in vivo studies, the composition is fed to an animal (eg, a mouse), injected, or topically applied, and then the composition, skin cancer cell survival, proliferation, metastasis, or skin cancer. Or evaluate the effect of one or more of the associated diseases or disorders on the symptoms. Based on this result, the appropriate dose range, frequency and route of administration can be determined.

The compositions useful herein may be used alone or in combination with one or more other anti-epithelial cancer agents or one or more additional therapeutic agents. This anti-epithelial cancer agent or additional therapeutic agent is a food, beverage, food additive, beverage additive, food ingredient, beverage ingredient, nutritional supplement, nutritional product, medical food, functional food, functional cosmetics, medical equipment. , May be medical supplies, drugs or medicines, or may include. This anti-epithelial cancer agent or additional therapeutic agent preferably comprises one or more of the symptoms of one or more neoplastic diseases or disorders or one or more neoplastic diseases or disorders. It benefits subjects to whom this anti-epithelial cancer agent or additional therapeutic agent is administered, which is effective in attenuating or otherwise. Preferred therapeutic agents include therapeutic food factors, immunogenic or immunostimulators, wound healing agents and the like.

The additional anti-epithelial cancer agents or therapeutic agents listed above (both food-based agents and pharmaceuticals) may also be utilized in the methods according to the invention, in which the additional anti-epithelial cancer agents or therapeutic agents are referred to. It should be understood that the compositions useful herein are administered separately, simultaneously or sequentially.

As will be recognized, the dose of composition administered, duration of administration and general administration regimen will be the severity of the subject's symptoms, the type of disorder treated, the mode of administration selected, and the subject's age and gender. And / or may vary between subjects depending on variables such as overall health. However, as a general example, a composition useful herein is administered from about 1 mg to about 5000 mg / kg body weight per dose or daily, with 1 mg to about 4000 mg / kg body weight herein. A useful composition is administered, 1 mg to about 3000 mg / kg body weight 1 kg of the composition useful herein is administered, and 1 mg to about 2000 mg / 1 kg body weight of the composition useful herein is administered, 1 mg to 1 mg. The compositions useful herein are administered at about 1000 mg / kg body weight, preferably from about 5 to about 100 mg / kg per day. In one aspect, administration is a composition useful herein of about 0.05 mg to about 250 mg / body weight 1 kg.

In various embodiments, a composition sufficient to deliver about 0.001 mg to about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof per kg body weight is administered and 1 kg body weight. Per, per dose or per day, about 0.001 mg to about 40 mg / body weight 1 kg, about 0.001 mg to about 30 mg / body weight 1 kg, about 0.001 mg to about 20 mg / body weight 1 kg, about 0.001 mg to about 10 mg / body weight 1 kg, about 0.001 mg to about 5 mg / body weight 1 kg, about 0.001 mg to about 1 mg / body weight 1 kg, about 0.001 mg to about 0.5 mg / body weight 1 kg, about 0.001 mg to about 0.1 mg / Administer a composition sufficient to deliver 1 kg body weight or about 0.001 mg to about 0.05 mg of the compound of formula (I) or a pharmaceutically acceptable salt or admixture thereof.

It should be recognized that administration can include single doses (eg, once daily) or, where appropriate, administration in many separate divided doses. One of ordinary skill in the art should understand that, in view of the present technology and the present disclosure, it is possible to determine an effective dosing regimen (eg, dose and timing of dosing) for a given condition without undue experimentation.

The present invention also comprises cyclos of one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, optionally with propolis or substances comprising propolis. It also relates to a dietary composition, a functional food composition, a functional cosmetic composition or an oral pharmaceutical composition comprising, in combination with dextrin. In certain embodiments, the composition is about 1-99% by weight, rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or admixtures thereof. It consists essentially of propolis, propolis resin or propolis resin extract and about 1-80% by weight cyclodextrin. For example, the composition is about 20-80% by weight of propolis, propolis, rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof. It consists essentially of a resin or propolis resin extract and about 20-80% by weight cyclodextrin. In another example, the composition is about 20-40% by weight of propolis rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. , Propolis resin or propolis resin extract and approximately 60-80% by weight cyclodextrin.

Propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof encapsulated with cyclodextrin. , Or a dietary composition, a functional food composition, a functional cosmetic composition or an oral pharmaceutical composition comprising or comprising propolis, a propolis resin or a substance containing a propolis resin extract. .. In certain embodiments, the composition is about 1-30% by weight, rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or admixtures thereof. It consists essentially of propolis, propolis resin or propolis resin extract and about 70-99% by weight cyclodextrin. For example, this composition is about 10-25% by weight of propolis, propolis, rich in one or more compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof. It consists essentially of a resin or propolis resin extract and about 75-90% by weight cyclodextrin. In another example, the composition is about 20-30% by weight of propolis rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. , Propolis resin or propolis resin extract and approximately 70-80% by weight cyclodextrin.

In one aspect, the composition is a propolis, propolis resin or propolis resin extract rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. , Or a propolis fraction rich in one or more compounds of formula (I) or one or more pharmaceutically acceptable salts or solvates thereof. In one aspect, the composition comprises at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 99% by weight of propolis, propolis resin. It comprises a propolis resin extract or a propolis fraction and the effective range can be selected from any of these values (eg, about 1 to about 25% by weight, about 1 to about 30% by weight, about 5 to about 30% by weight, About 15 to about 30% by weight, about 20 to about 30% by weight, about 25 to about 30% by weight, about 10 to about 50% by weight, about 15 to about 50% by weight, about 40 to about 99% by weight, about 45. ~ About 99% by weight, about 50 ~ about 99% by weight, about 55 ~ about 99% by weight, about 60 ~ about 99% by weight, about 65 ~ about 99% by weight, about 70 ~ about 99% by weight, about 75 ~ about 99% by weight, about 80-about 99% by weight, about 85-about 99% by weight, about 90-99% by weight or about 95-about 99% by weight).

In one aspect, the composition comprises a cyclodextrin (eg, alpha-cyclodextrin and / or gamma-cyclodextrin). In one aspect, the composition is at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or at least about 90. It contains% by weight cyclodextrin and the effective range can be selected from any of these values (eg, about 1 to about 99% by weight, about 5 to about 99% by weight, about 10 to about 99% by weight, about 15 to). About 99% by weight, about 20 to about 99% by weight, about 25 to about 99% by weight, about 30 to about 99% by weight, about 35 to about 99% by weight, about 40 to about 99% by weight, about 45 to about 99. Weight%, about 50 to about 99% by weight, about 55 to about 99% by weight, about 60 to about 99% by weight, about 65 to about 99% by weight, about 70 to about 99% by weight, about 75 to about 99% by weight. , About 80-about 99% by weight, about 85-about 99% by weight, about 90-about 99% by weight or about 95-about 99% by weight).

When used in combination with another anti-epithelial cancer agent or therapeutic agent, the composition useful herein and another anti-epithelial cancer agent or therapeutic agent may be administered simultaneously or sequentially. May be. Co-administration may include administration of a single dosage form containing all components, or administration of separate dosage forms at substantially the same time. Consecutive doses preferably include administration according to different schedules such that there is an overlap in the time period in which the composition useful herein is given to the other therapeutic agent.

In addition, it is contemplated that a composition according to the invention may be formulated with additional active ingredients that may be beneficial to the subject in certain cases. For example, therapeutic agents that target the same or different aspects of the disease process may be used.

Therefore, the "food and beverage containing the antiepithelial cancer composition" of the present invention can be used for general foods and health foods. Since the anti-epithelial cancer composition of the present invention hides the taste of propolis, the composition can be eaten as it is or in the form of powder. This composition can be used as an ingredient or ingredient in cakes, biscuits, cookies, chocolate, confectionery and other confectionery (eg, drops or chewing gum). This composition may be added to water as a beverage and may be used as a taste modifier for beverages (eg milk, tea, coffee, hot chocolate, etc.) and as an ingredient or raw material for fruit juice beverages, sports drinks and the like.

Exemplary anti-epithelial cancer compositions and methods of preparing such compositions will now be described with reference to the following examples.

Example 1: Initial Bioassay-Induced Fraction of Propolis Tincture This example illustrates an assessment of the anti-gastrointestinal cancer activity of the propolis fraction produced by preparative chromatography. This study was performed using a proliferation assay on the human colon cancer adenocarcinoma cell line DLD-1.

Generation of Propolis Tincture Fraction by Column Chromatography The fraction was washed with methanol (Methanol) (200 ml) and then equilibrated with 20% aqueous ethanol (EtOH) (500 ml) Merck Richroprep CI8 reverse phase stationary phase (16 x 4 cm). ) Was performed using a glass column filled with. A dry propolis tincture solid (5.446 g) dissolved in EtOH (5 ml) was loaded onto the top of this column using a piston pump. Elution was performed as a stepwise gradient (250 ml) consisting of 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90% aqueous EtOH followed by two 100% EtOH steps. , Then eluted with 2-propanol (IPA), ethyl acetate (EtOAc), acetone and chloroform (CHCl3). Solvents were removed from the various fractions on a rotary evaporator under vacuum and then lyophilized overnight. Pool two 100% EtOH fractions and pool the remaining four non-polar fractions (IPA, EtOAc, Acetone and CHCl3) as well for biological assay work due to their relatively low mass. did. These fractions are taken from the percentage of ethanol used in the elution step from this column (eg 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90% aqueous EtOH and 100%. It is shown in Table 1 according to EtOH).

(Table 1) Image quality for propolis and number of test samples

Materials and Methods for Anti-Gastrointestinal Cancer Antiproliferative Assays for DLD-1 Human Colon Adenocarcinoma Cells, KYSE-30 Human Esophageal Shirae Epithelial Cell Cancer and NCI-N87 Human Gastric Cancer Obtained by fractionation of dry solids of propolis tincture. The test samples shown in Table 1 above were evaluated for their ability to regulate viability and proliferation of human colonic rectal adenocarcinoma cells (DLD-1) as assessed by the MTT assay. The bioassay also included a dry solid starting material for propolis tincture. This study included the positive control 5-fluorouracil (5-FU) in addition to the unsupplemented cell control (negative control). In later examples, test samples were also evaluated for their ability to regulate viability and proliferation of human esophageal cells (KYSE-30) and human gastric cancer cells (NCI-N87) as assessed by the MTT assay.

Description of test materials and test methods Human gastrointestinal cancer cell lines DLD-1, KYSE-30 and NCI-N87 were revived from cryopreservation and cultured in the presence of test and reference samples. The culture conditions for these cells were described by the supplier of these cells (ATCC). The culture was then subjected to an MTT assay to determine the effect of the sample on cell proliferation.

The methodology was based on the procedure reported by:
Smolka, AJ, Goldenring, JR, Gupta, Sand Charles E Hammond, CE. Inhibition of gastric H, K-ATPase active and gastric epithelial cell IL-8 secretion by the pyrrolizidine ML 3000. (2004). BMC Ghostology. 4: 4.
Challenger, Pand Menard, D (2005). Estabulishment of Human Gastric Epithelial (HGE) Cell Lines Exhibiting Barrier Function, Progenitor, and Prezymogenic Chemicals. Journal of Cellular Physiology 202: 263-274.
Trainer, D.I. L. , Kline, T.I. , McCabe, F.I. L. , Faucette, L. et al. F. , Field, J. et al. , Chaikin, M. et al. , Anzano, M. et al. , Rieman, D.I. , Hoffstein, S.A. , Li, DJ. , Gennaro, D.I. , Buscarino, C.I. , Lynch, M. et al. , Poste, G.M. And Greig, R.M. (1988). Biological characterization and oncogene expression in human colorectal cancer cells lines. International Journal of Cancer 41: 287-296.
Shimada, Y, Imamura, M, Wagata, T, Yamaguchi, N, Tobe, T.I. (1992) Encryptation of 21 newly staffed Esophageal Cancer Cell Lines. Cancer 69: 277-284.
Sutter, AP, Hopfner, M, Heater, A, Master, K, Scherubi, H. et al. (2006) Targeting the epithelial growth factor factor receptor by erlotinib (Tarceva ^TM ) for the treatment of esophageal cancer. Inter, J Cancer. 118: 1814-1822
Paryi, I. (1989) Heterogeneity of the Response to Inducers of Differentiation and to Cytostasis of Tumor Cell Populations. Pathology Research & Practice. 184: 11-17.
Fritzche, C, Zeller, G, Knaup, KX, Roemer, K. et al. (2004) No anti-apoptotic effects of single copies of mutant p33 genes in drug-treated tumor cells. Anti-Cancer Drugs. 15: 679-688.
Yang, Y, Zhou, Z, He, S, Fan, T, et al. (2012) Treatment of prostate cancer with (Galectin-3) -targeted HPMA copolymer- (G3-C12) -5-Fluorouracil conjugates. Biomaterials. 33: 2260-2271.
Nakagawa, Y. et al. , Iinuma, M. et al. , Naoe, T. et al. , Nozawa, Y. et al. And Akao, Y. (2007). Chargerized mechanism of α-mangosteen-induce cell death: Caspase-independent apoptosis with release of endoclearase-G from mitochondria Bioorganic & Medicinal Chemistry 15: 5620-5628.
Minegaki, T.M. , Takara, K. et al. , Hamaguchi, R.M. , Tsujimoto, M.D. And Nishiguchi, K.K. (2013). Factors affecting the sensitivity of human-derivated esophageal cell lines to 5-fluorouracil and cisplatin. Oncology Letters 5: 427-434.
Nakamura, A.M. , Nakajima, G.M. , Okuyama, R.M. , Kuramochi, H. et al. , Kondoh, Y. et al. , Kanemura, T.I. , Takechi, T.I. , Yamamoto, M. et al. And Hayashi, K.K. (2014). Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cancer cells with upregulated expression. Gastric Cancer 17: 188-195.
Tankiewicz-Kwedlo, A.M. , Paulak, D.I. , Domaniewski, T.I. And Buczko, W.M. (2010). Effect of erythropoietin, 5-fluorouracil and SN-38 on the group of DLD-1 cells. Pharmaceutical Reports 62: 926-937.

Sample Preparation A working solution was prepared by dissolving the test fraction in 15% ethanol (ETOH) / HBSS to a solid concentration of 2 mg / ml.

Experimental procedure characterization of test system 1. Human colorectal adenocarcinoma cells were obtained from ATCC (CCl-221, DLD-1).
2. 2. Human gastric cancer cells were obtained from ATCC (CRL-5822, NCI-N87).
3. 3. Human esophageal squamous epithelial cell carcinoma cells were obtained from Sigma Aldrich (ECACC, KYSE-30).
4. The DLD-1 cell medium obtained from GIBCO was Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 100 U / ml penicillin and 100 mg / ml streptomycin. This medium was stored at 4 ° C.
5. The NCI-N87 cell medium obtained from Sigma was RPMI-1640 medium modified to contain 2 mM L-glutamine, 10 mM HEPES, 1 mM sodium pyruvate, 4500 mg / L glucose and 1500 mg / L sodium bicarbonate. This medium was stored at 4 ° C.
6. The KYSE-30 cell medium obtained from Sigma was Ham's F12: RPMI-1640 (50:50) medium modified to contain 2 mM L-glutamine. To this complete medium was added 10% FBS, 100 U / ml penicillin and 2.5 μg / ml gentamicin. This medium was stored at 4 ° C.
7. A penicillin-streptomycin solution (stored at −20 ° C.) consisting of 10000 units / mL penicillin in 0.9% NaCl and 10 mg / ml streptomycin was obtained from Sigma (# P-0781).
8. A trypsin-EDTA solution consisting of 0.25% trypsin / EDTA was obtained from Invitrogen (15400054).
9. Phosphate buffered saline (PBS) was prepared in-house.
10. Hanks Balanced Salt Solution (HBSS) (stored at 4 ° C.) was obtained from GIBCO (14185-052).
11. Fetal bovine serum (stored at −20 ° C.) was obtained from GIBCO (10091-148).
12. The MTT reagent (100 mg / vial) (M-2128) obtained from SIGMA was dissolved in PBS at 10 mg / ml and stored at −20 ° C. A 5 mg / ml MTT solution was prepared with PBS and stored as a working solution at 4 ° C.
13. 20 g of sodium dodecyl sulfate (SDS) is dissolved in 100 mL of redistilled water (DDW), 90 mL of dimethylformamide is added, the pH is adjusted to 4.7 with glacial acetic acid and then diluted with DDW to a final volume of 200 ml. To prepare an MTT lysis buffer consisting of 10% SDS / 45% dimethylformamide.
14. 5-Fluorouracil (5-FU) was obtained from Sigma (F-6627). Working solutions with 15% ETOH / HBSS were prepared as needed and then diluted to the required concentrations just prior to the bioassay.

Medium Preparation Medium for each growth of the cell line is shown above. Each medium was prepared according to the manufacturer's instructions and supplemented with a penicillin-streptomycin solution (10 ml per liter). FBS (10%) was added immediately before use.

Cell culture 1. Each of the cell lines was resuscitated from cryopreservation.
2. 2. After initial growth using the medium described above (see Medium Preparation), the cultures were subcultured using trypsin-EDTA as described below. The medium was removed, 5 ml of trypsin-EDTA solution was added and incubated for 5 minutes or at 37 ° C. until all cells were exfoliated. Equal volumes of DMEM medium were added to neutralize trypsin, and the culture was centrifuged at 300 g (1200 rpm) at 4 ° C. for 5 minutes.
3. 3. The supernatant was decanted and the cell pellet was resuspended in medium DMEM, FBS (10%), penicillin (100 units / ml), streptomycin (100 μg / ml). Cells were cultured in 5% CO ₂ /95% air at 37 ° C.
4. After reaching confluence, cells were detached using trypsin-EDTA and centrifuged as described in 2 above.
5. The supernatant was discarded and the cells were resuspended in DMEM and the supplement described in 3 above with 1.0 × 10 ⁴ cells per ml.
6. 180 μl of cells (1,800 cells / well) or medium was added to each well of the three 96-well plates. The plates were incubated for 48 hours at 37 ° C. in 5% CO ₂ /95% air and this condition was sufficient for cell attachment.
7. To each well was added 20 μl of each of the test samples or positive controls. In the case of "medium" or "cell only" controls, 20 μl of 15% ETOH / HBSS was added to each well. Each sample was evaluated on 3-6 iterations and controls on each of the 3 microtiter plates were evaluated on 3-9 (combined 3 iterations) iterations. The final concentration of the sample in each well was 200 μg / ml unless otherwise noted.
8. The total volume in each well was 200 μl.
9. Plates were incubated at 37 ° C. in 5% CO ₂ /95% air for 19 hours.

Cell proliferation assay 1. At the completion of the incubation, 20 μl of MTT working solution (5 mg / ml) was added to all wells and incubated in 5% CO ₂ /95% air at 37 ° C. for 3-4 hours.
2. 2. During this incubation period, we noticed an unexpected strong color in some of the wells of some samples, both in the wells of cells and samples and in the blank wells of samples and media. At the end of this period, the supernatant was removed from each well, each well was gently washed twice with HBSS to remove purple, and then MTT lysis buffer was added as described in step 3 below.
3. 3. Then 100 μl of MTT lysis buffer was added and the plates were incubated overnight at 37 ° C. in 5% CO2 / 95% air. The plate was centrifuged at 1200 rpm for 10 minutes to pellet any residual insoluble material. 200 μl of aliquot from each well was transferred to a fresh 96-well plate. This plate was read at 570 nm with a VersaMax microplate reader.
4. The results were expressed as the proliferation rate of cells cultured in the presence of the sample compared to the cell-only control. Blank readings were subtracted from all wells as background readings.

Results A summary of the effects of control and test samples on the proliferation of DLD-1 cells with respect to the propolis fractions S # 1 to S # 10 and the comparative propolis dry solid S # 11 is shown in Table 2 below, in which NC = Negative control (cells only), PC = positive control (5-fluorouracil, tested at 7.50 ng / ml). In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 2) Effect of propolis fraction sample on DLD-1 cell proliferation

The most active propolis fractions were found to be fractions S # 1, S # 2, S # 5 and S # 8. The propolis fractions S # 1, S # 2 and S # 5 contained known propolis phenols and flavonoids and were therefore not investigated further in this study. Further studies were performed to determine the compounds present in the propolis fraction S # 8 (which was found by HPLC to be free of any previously identified phenolic compounds). This study will be described in Example 2.

Example 2: Bioassay-Induced Fraction of Non-Phenolic Fractions This example illustrates a further bioassay-induced fraction of the propolis fraction S # 8 prior to compound identification. Four additional fractions numbered S # 28-S # 31 were generated. This study was performed using the proliferation of colon cancer adenocarcinoma cell line DLD-1 by the MTT assay, which was Example 1.

Preparative HPLC for producing fine fractions S # 28-S # 31
The 90% aqueous EtOH-eluted fraction (propolis fraction S # 8) produced for Example 1 was further fractionated by preparative HPL. Propolis fraction S # 8 is dissolved in neat EtOH and then using a Phenomenex Synergi C-12 column (4 μ, -RP Max 80A 250 x 30 mm) using a Gilson 321 preparative pump and an Agilent 1100 series diode array detector. Was subjected to chromatography by preparative HPLC. An injection volume of 0.5-1.5 ml was used. A flow rate of 20 ml / min was used. Solvents were 80% aqueous MeOH (including 0.1% MeOH) and EtOAc / MeOH (4: 1 volume / volume). The first eluent composition consisted of 80% aqueous methanol. After retaining the solvent composition for 5 minutes under initial conditions, the EtOAc / MeOH solvent concentration was linearly increased to 100% over 35 minutes. This chromatography was performed at room temperature (18-20 ° C.). Fractions were also manually collected with online detection performed at 210 nm, 268 nm and 327 nm and also by Evaporative Light Scattering Detection (ELSD). The main component of this fraction is completely non-polar and elutes later in the chromatogram, providing minimal UV absorption at the wavelengths generally used for analysis of other propolis fractions containing phenol (ie 268 and 327 nm). Indicated. However, ELSD revealed a complex mixture of ingredients. Due to the destructive nature of ELSD, preparative HPLC fractions were manually collected by online detection performed at 210 nm. During this run, four fractions were collected and all prepared for the biological assay, as chromatography did not produce a clear single peak, but rather wide up and down at baseline.

Materials and Methods for the DLD-1 Colorectal Cancer Antiproliferation Assay The test samples shown in Table 3 below regulate the viability and proliferation of human colorectal adenocarcinoma cells (DLD-1) as evaluated by the MTT assay. Evaluated in terms of ability to do. This study included positive control 5-fluorouracil (5-FU) in addition to unsupplemented cell controls (NC, negative control). The concentration of 5-FU was increased from Example 1 to elicit a stronger antiproliferative response. The DLD-1 antiproliferation assay was performed as described in Example 1.

(Table 3) Test sample

The sample was dissolved in 15% EtOH in HBSS at 2 mg / ml as a working solution. In this assay, the final concentration of the sample was 200 μg / ml and the final EtOH concentration was 1.5%.

Results and discussion Table 4 outlines the effects of positive controls on cell proliferation and test samples after 24-hour incubation, in Table 4, NC = negative controls (cells only), PC = positive controls (5-fluorouracil). , 0.65 and 1.95 μg / ml). In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 4) Effect of propolis fine fraction sample on DLD-1 cell proliferation

All of the propolis fractional samples tested inhibited the growth of DLD-1 colon cancer cells. The most active fraction was S # 30 90% F3, which was completely cytotoxic and cytotoxic at the concentrations tested. Further research was performed in Example 3 to identify the properties of the bioactive compounds present in the test samples used in Examples 1 (Polopolis fraction S # 8) and 2 (Propolis fine fraction S # 30).

Example 3: Identification of glycerides in propolis as an active compound This example is from the NZ propolis resin fraction equivalent to Examples 1 (propolis fraction S # 8) and 2 (propolis fine fraction S # 30). The isolation and identification of novel dihydroxy fatty acid glycerides will be described. 1 gram of 40% propolis tincture containing 40% propolis resin (400 mg dry solid) was fractionated using a silica gel column using a stepwise solvent gradient to give 14 fractions with the weight distribution shown in Table 5. Generated. Each fraction was analyzed by UHPLC using both UV (268 nm for phenol detection) and ELSD detector (for detection of all compounds). The propolis resin and selected fractions were also analyzed by LC-MS to enable structural elucidation. The purified fine fractions were also analyzed by NMR. The column is washed sequentially with hexane, hexane / diethyl ether and diethyl ether and from silica (1-2; 3-7; 8-9, respectively) to the majority of the phenolic material (eg flavonoids, caffeate and ferulic acid esters). Elution. A brown fraction remained on this silica. This brown elution began with the use of ethyl acetate (fractions 11-12). Most of the remaining dark color was then eluted with acetone and methanol (fractions 13, 14). The mass distribution is such that most of the propolis mass is present in the light yellow diethyl ether fraction, but a significant proportion of the total mass is eluted in the ethyl acetate-eluted fractions (fractions 11 and 12). Show that you did. The water-soluble material was recovered in fractions 13, 14 or retained on the column.

(Table 5) Weight and solvent gradient for silica gel fraction of propolis

Results and Discussion The novel compound appeared as a sharp peak in the 34-44 minute region of the ELSD chromatogram of fractions 12 and 13. Late peaks observed by ELSD (sharp and well separated) could be associated with a set of peaks seen in crude propolis and LC-MS runs of enriched fractions 12 and 13. UV absorption was not associated with these peaks. Mass spectrometry (MS) shows good peaks in cation mode with M + 1 and M + Na peaks observed. The main components of this set of compounds have molecular weights of 460, 474, 488 and 502 and are equal to homologous series with different components on the methylene group. All of this mass spectrum had a common peak in atomic mass units (amu) of 159 and 117. In anion mode, this compound had quasi-molecular ions at M + 45 due to the formic acid adduct. High resolution MS showed the molecular formula of C25H48O7 for compounds with a molecular weight of 460 and extra methylene for others in this homologous series. The fine fractions of the coarse fractions 12 and 13 were then completely acetylated to facilitate separation of the compound of interest and to obtain clearer spectroscopic data. The mass spectrum of the hyperacetylated mixture generally showed that this compound formed triacetates as shown by a molecular weight increase of 3 × 42 atomic mass units.

The first chromatographic fraction described above was repeated several times to produce more enriched fractions 11-13. The compound of interest was also easily separated from these enriched fractions by silica gel chromatography to give sufficient material for NMR analysis. The spectrum showed the presence of four acetate groups (eg, a single acetate present in some of the natural compounds). Substituted glycerol was present, and the acid attached to this glycerol was also hydroxylated at the 3-position. The rest of this molecule was composed of a fatty acid chain that also had a second hydroxyl group. This fatty acid is the main compound dihydroxy C20, C21, C22 or C23. Therefore, this compound is a glyceride.

GC-MS analysis of the TMS-treated glyceride-rich fraction produced by reverse-phase column chromatography showed that the natural mixture of hydroxylated fatty acid lipids present in propolis was considerably complex. This fraction had common fatty acids (palmitic acid, oleic acid and stearic acid) already known to be present in propolis along with monoglycerides. This complexity was reduced by base hydrolysis to remove both the glycerol and acetyl moieties to give four major and some minor dihydroxy fatty acids. This was consistent with the structural type described above, but the location of the acetyl group was not identified. Combining this with the fatty acid range and the position / character isomer of the hydroxyl group yields a number of analogs. The major compounds identified by chromatographic isolation followed by structural elucidation using MS and NMR are monoacylglycerides of dihydroxy C20, C21, C22 or C23 fatty acids (esterification of glycerol at the C1 position). there were. The fatty acids in this monoglyceride were mainly linear C20 to C22. This fatty acid was hydroxylated at the C3 position, the second hydroxyl group was separated from the first by at least one methylene group and was not present on the final methyl group of this fatty acid. The glycerol moiety may be acetylated with one or both hydroxyls at the C2 and C3 positions. Further research was performed in Example 4 to determine the position of the acetyl group and the position of the second hydroxyl group on this fatty acid.

Example 4: Generation of glyceride concentrate and isolation and purification of glyceride In this example, the position of the second hydroxyl group on this fatty acid was determined and the placement of the acetyl group was determined as well. Individual glyceride compounds were also isolated. A large-scale extract was prepared from 1.1 kg of delowed propolis resin using ethyl acetate as a solvent. The propolis resin was coarsely chopped and immersed in ethyl acetate at room temperature with mechanical stirring for 2 hours. The solvent containing the dissolved extract was filtered but not concentrated. Approximately 20% of this extract solution was subjected to chromatography using silica gel, the extract was first absorbed into a portion of silica gel and then the ethyl acetate was evaporated using a rotary evaporator. This pre-absorbed solid is then applied to the top of a large silica gel column, the column is eluted with 1: 1 hexane / ether, an 8 x 150 ml fraction is collected, and then the column is subjected to four additional 150 ml with diethyl ether. After elution into the fraction, elution with ethyl acetate was started. The four ethyl acetate fractions collected (fractions # 13 to # 16) were much darker in color than the previous fractions. The final fraction (# 17) was collected after elution with acetone. The progress of this purification process was followed using silica TLC (phosphomolybdic acid in ethanol, followed by visualization using heating) and LC-MS. The glyceride-rich fractions from silica gel chromatography were then combined and subjected to reverse phase C18 column chromatography using an acid-free mixture of water and ethanol to give the final glyceride-rich fraction (GLY-conc). This process was repeated with more ethyl acetate extracts as needed.

Analysis of all fractions by LC-MS showed that ethyl acetate fractions # 13- # 16 and acetone fractions # 17 contained the major glyceride compounds. These fractions were also rich in brown material, consistent with Example 3. Fractions # 13 and # 14 are summarized, and # 15 and # 16 are also summarized. The summarized # 13 / # 14 fractions were used for structure identification as described below. About 100 mg of this # 13 / # 14 mixture was mixed with 4 ml of THF: MeOH: H2O and 55 mg of LiOH. This was stirred at ice temperature for 30 minutes and then at room temperature for 48 hours. The reaction mixture was acidified with acetic acid and extracted with chloroform. The dried extract was then esterified with diazomethane and subjected to silica gel chromatography (ethyl acetate / hexane). Fractions containing one major spot (1: 1 EtOAc: Rf about 0.3 with hexanes, phosphomolybic acid in ethanol and visualization by heating) were collected. The purified sample was then analyzed by GC-MS after treatment with BSTFA. The nine free fatty acid peaks numbered 4-12 resulting from the hydrolysis of glycerides in the MS spectrum were homologous. Major peak 4 has a characteristic peak at 383 (corresponding to the loss of methyl and TMSOH), followed by major peaks 5 (397), 7 (411), 10 (425), 11 (439) and 12 ( 453) was a C19-C24 dihydroxy fatty acid (methyl ester TMS ether). Another feature was the fragment ions at m / z 301 and 247 found at all peaks. These fragments (particularly the 301 fragment) are those of the 3,8-dihydroxyate TMS ether obtained by saponification, methylation and sialation of 3-acetoxy, 8-hydroxy fatty acid glycerol esterified at the C2-position on glycerol. It is a feature [Asai, T. et al. , Hara, N. et al. , Kobayashi, S.A. , Kohsima, S.A. , Fujimoto, Y. et al. (2009). Acylglycerols (= glycerides) from the glandular trichome exudate on the leaves of Paulownia tomentosa. Helvetica Chemica Acta. 92: 1473-1494]. Other possible dihydrochiates 3,6; 3,7 and 3,9 have different fragmentation patterns. Therefore, the dihydroxy acid in the glyceride fraction is a 3,8-dihydroxy fatty acid of C19 to C24. Relative peak sizes indicate that C20 and C22 chain lengths were the major compounds. Minor peaks 6, 8, 9 and 13 with almost identical MS fragmentation to larger peaks were also seen. Peak 9 was very similar to 10 and peak 12 was very similar to 13. These minor peaks were the isoforms of C22 and C24 acids, i.e., branched methyl at the end of the fatty acid. This is consistent with the evidence from NMR of the peracetylated compound suggesting a small amount of methyl branching.

The combined # 15/16 fractions were then used for preparative HPLC and subsequently for Sephadex LH20 size exclusion chromatography to use the two monoacetate compounds GLY-1Ac-1 and GLY-1Ac-2 (respectively). C20 and C21 dihydroxy fatty acid monoacetate) were obtained. Fraction # 17 was used for preparative HPLC and subsequently for Sephadex LH20 size exclusion chromatography to use the three no-acetate compounds GLY-0Ac-1, GLY-0Ac-2 and GLY. -0Ac-3 (C20, C21 and C22 dihydroxy fatty acid monoglycerides, respectively) was obtained. The progress of separation was followed using HPLC with ELSD and the purity of the isolated individual compounds was evaluated by HPLC, LC-MS and NMR to be> 95%.

Example 5: Generation of glyceride concentrate, free fatty acid, methyl ester, diacetate, peracetate and cyclodextrin complex Hydrolysis of the glyceride concentrate sample obtained in Example 4 was carried out by Reis et al. (Reis, MG). ., De Faria, AD, Do Amaral, MDCE, Marsialoli, AJ (2003). Performed as described in Tetrahedron Letters 44: 8519-8523) to produce free fatty acids (FFA-conc). About 100 mg of glyceride concentrate was mixed with 4 ml of THF: MeOH: H2O and 55 mg of LiOH. This was stirred at ice temperature for 30 minutes and then at room temperature (RT) for 48 hours. The reaction mixture was acidified with acetic acid and extracted with chloroform. This free fatty acid mixture was purified using silica gel chromatography (ethyl acetate / hexane).

A sample of the purified free fatty acid mixture was also methylated to produce the dihydroxy fatty acid methyl ester (ME-conc). Methylation was performed by adding a diazomethane solution (Aldrich, trimethylsilyldiazomethane, 2.0 M hexane solution) to 10 mg of the free fatty acid mixture. After reacting at room temperature for 1 hour, the reaction was quenched with acetic acid and the solution was evaporated to dryness under N2. The methyl ester mixture was purified using silica gel chromatography (ethyl acetate / hexane). Fractions containing one major pot (1: 1 EtOAc: Rf about 0.3 with Hex, phosphomolybdic acid in ethanol, followed by thermal visualization) were collected.

Dihydroxyfatty acid glyceride diacetate (GLY-2Ac- 1 mix) was prepared. The reaction mixture was purified to give one spot on TLC.

Peracetylation of this glyceride-rich fraction (PerAc-conc) is performed by dissolving this partially purified glyceride fraction (about 150 mg) in acetic anhydride (20 mL) and adding a small amount of dimethylaminopyridine. did. After stirring overnight at room temperature, this reaction was completed by adding methanol and toluene (about 20 mL each) and evaporating to dryness using a rotary evaporator. The residue was chromatographed on silica gel using a hexane / ethyl acetate mixture to give a purified peracetate mixture (about 80 mg).

The cyclodextrin complex of the glyceride concentrate obtained in Example 4 was produced as follows. Approximately 400 mg of glyceride concentrate was accurately weighed into the flask. Then, 1.2 g of ethanol was added to this vial, and the contents were stirred to dissolve the solid to prepare a 25% by mass ethanol solution of glyceride. This glyceride was rapidly dissolved in ethanol. Approximately 300 mg of alpha, beta and gamma cyclodextrin were accurately weighed separately into the mortar. Approximately 400 mg of 25% glyceride tincture was then added to each mortar containing one of these cyclodextrins with a calibration syringe. The contents of each mortar were then mixed with a pestle into a uniform paste. Excess water was then added to each mortar and the contents were mixed until a uniform pale yellow dispersion of the complex in water was obtained. The contents of each mortar were placed in a weighed round-bottom flask. The contents of the flask were frozen by rotating the flask in a dry ice / acetone mixture. The contents of this flask were then lyophilized. From this flask, gamma-cyclodextrin glyceride complex (g-CD GLY conc) 370 mg; beta-cyclodextrin glyceride complex (β-CD GLY conc) 390 mg; and alpha-cyclodextrin glyceride complex (α-CD GLY conc). ) 360 mg was recovered.

Example 6: Antiproliferative activity of dihydroxy fatty acid glyceride against human skin cancer cell line: melanoma cell line A-2058 In this example, some of the glyceride compounds present in NZ propolis are human melanoma cell line A-2508. It is shown to have a novel anti-skin cancer activity against. This example also measures the antiproliferative activity of purified fractions and highly purified glycerides against human skin cancer cell lines and the activity of these test compounds against human melanoma cell line A-2058. In vitro bioassay methods are also described. The three human skin cancer cell lines were:
1) Human melanoma cell line (A-2058).
2) Human epidermis (squamous cell) carcinoma cell line (A-431).
3) Human basal cell carcinoma cell line (TE 354.T).

These cell lines were resuscitated from cryopreservation and cultured in the presence of test and reference samples. The culture was then subjected to an MTT assay to measure the effect of the sample on viability and proliferation of the cells. The average standard error percentage was evaluated and extreme outliers were removed when SEM%> 15. Preliminary statistical significance was assessed by independent Student's t-test with α ≤ 0.05 (with or without outliers). The methodology was based on the procedure reported by:
Ahn, NG, Campbell JS (1993). Metabolic labeling of mitogen-activated protein in A431 cells demonstrates phosphorylation on serine and threonine resides. Proc Natl Acad Sci. 90: 5143-5147.
Galan-Cobo, A et al (2014). Functional inhibition of aquaporin-3 with a gold-based complicated cells blockage of cell proliferation. J Cellul. Physiol. 229: 1787-1801.
Romei, MW, Kalinovsky, Jet al (2013) Effect of a nutrient mixture on matrix metalloproteinase-9 dimers in various human cancer cell line. Inter J Oncol. 44: 936-942.
Huang, HC, Lin, MK et al (2013). Cardenolides and bufadienolide glycosides from Kalanchoe tubiflora and evolution of cytotoxicity. Planta Medica. 79: 1362-1369.
Tilli, CMLJ, Stavast-Koy, AJW et al (2003). The garlic-derivated organosulfur component ajoene decreases basal cell carcinoma tumor size by apoptosis. Arch Dermatol Res. 295: 117-123.

Sample Preparation The test sample was dissolved in 15% ethanol (EtOH) / HBSS to prepare a working solution, which was then diluted 10-fold to give a final concentration of 50 μg / ml cells unless otherwise noted. ..

Experimental procedure characterization of test system 1. Human melanoma cell lines (A-2058, ATCC CRL11147) were obtained from ATCC, Bethesda, MD, USA.
2. 2. Human squamous cell carcinoma cell lines (A-431, ATCC CRL1555) were obtained from ATCC, Bethesda, MD, USA.
3. 3. Human basal cell carcinoma cell lines (TE 354.T, ATCC CRL7762) were obtained from ATCC, Bethesda, MD, USA.
4. Dulbecco's Modified Eagle's Medium (DMEM) was obtained from GIBCO (12100-038). Prior to use, 10% fetal bovine serum (FBS), 100 U / ml penicillin and 100 mg / ml streptomycin were added.
5. A penicillin-streptomycin solution (stored at −20 ° C.) consisting of 10000 units / ml penicillin and 10 mg / ml streptomycin in 0.9% NaCl was obtained from Sigma (# P-0781).
6. A trypsin-EDTA solution consisting of 0.25% trypsin / EDTA was obtained from Invitrogen (# 15400054).
7. Phosphate buffered saline (PBS) was prepared in-house.
8. Hanks Balanced Salt Solution (HBSS) (stored at 4 ° C.) was obtained from GIBCO (# 14185-052).
9. Fetal bovine serum (FBS) (stored at −20 ° C.) was obtained from GIBCO (# 10091-148).
10. MTT reagent (100 mg / vial) was obtained from SIGMA (M-2128), then dissolved in PBS at 10 mg / ml and stored at −20 ° C. A 5 mg / ml MTT solution was prepared with PBS and stored as a working solution at 4 ° C.
11. MTT lysis buffer: 10% SDS / 45% dimethylformamide was prepared by dissolving 20 g of sodium dodecyl sulfate (SDS) in 100 ml of redistilled water (DDW) and then adding 90 ml of dimethylformamide to this solution. The pH was adjusted to 4.7 with glacial acetic acid and DDW was added to a final volume of 200 ml.
12. 5-Fluorouracil (5-FU) was supplied by Sigma (F-6627). Three working solutions were prepared at 19.5 μg / ml, 6.5 μg / ml and 1.95 μg / ml dissolved in 15% ethanol / HBSS. The final concentrations were 1.95 μg / ml (15 μM), 0.65 μg / ml (5 μM) and 0.195 μg / ml (1.5 μM).

Medium Preparation Cell culture conditions were suggested by the cell supplier (ATCC). The medium for each growth of the cell line was DMEM shown above. Medium was prepared according to the ATCC instructions and supplemented with penicillin-streptomycin solution (10 ml per liter). FBS (10%) was also added immediately before use.

Cell culture:
1. 1. Each of the cell lines obtained from the American Type Culture Collection USA was resuscitated from cryopreservation.
2. 2. After initial growth in DMEM medium as described above, the cultures were subcultured using trypsin-EDTA. The medium was removed, 5 ml of trypsin-EDTA solution was added and incubated for 5 minutes or at 37 ° C. until all cells were exfoliated. Equal volumes of DMEM were added to neutralize trypsin, and the suspension was centrifuged at 300 g (1200 rpm) at 4 ° C. for 5 minutes.
3. 3. The supernatant was decanted and the cell pellet was resuspended in DMEM (containing FBS (10%), penicillin (100 units / ml), streptomycin (100 μg / ml)).
4. After reaching confluence, the cells were detached using the trypsin-EDTA described in 2 above and then centrifuged.
5. The supernatant was discarded and the cells were resuspended in DMEM and the supplement described in 3 above at various concentrations of cells per ml. The cell concentration of the A-431 culture was increased from 1x10 ⁴ cells to 5x10 ⁴ cells / ml, while the concentration of the other two cell lines (A2058 and TE 354.T) was 2x. It was increased to ¹⁰⁴ cells / ml.
6. For the three cell lines, 180 μl of cells or medium was added to each well of the 96-well plate. The plates were incubated at 37 ° C. with 5% CO ₂ /95% air for various periods of time to allow cells to adhere. In the case of the A-431 culture, the preincubation time was 3 hours, and the preincubation time of the other two cell lines (A2058 and TE 354.T) was 24 hours.
7. To each well, 20 μl of each or 5-FU of the test compound was added. To wells labeled "medium" or "cells only", 20 μl of 15% ETOH / HBSS was added. The number of times each test sample or control was evaluated is given in the table for this example.
8. The total volume in each well was 200 μl.
9. Each plate was further incubated at 37 ° C. in 5% CO ₂ /95% air for 24 hours.

Cell proliferation assay 1. At the completion of the incubation, 20 μl of MTT working solution (5 mg / ml) was added to all wells and the plates were incubated in 5% CO ₂ /95% air at 37 ° C. for 3-4 hours. Plates were monitored every 30-60 minutes and if a small number of cells showed the presence of crystals, lysis buffer was added as in step 2.
2. 2. 100 μl of MTT lysis buffer was then added and the plates were incubated overnight at 37 ° C. in 5% CO ₂ /95% air. The plate was centrifuged at 300 g (1200 rpm) for 10 minutes to pellet any residual insoluble material. 200 μl of aliquot from each well was transferred to a fresh 96-well plate. This plate was read at 550 nm with a VersaMax microplate reader.
3. 3. The results were expressed as the absorbance of cells cultured in the presence of the sample compared to the cell-only control case. Blank readings were subtracted from all wells as background readings.

Glycerol test samples GLY-1Ac-1 and GLY-1Ac-2 (dihydroxy fatty acid glycerides acetylated at the C3 position of glycerol, C20 and C21 fatty acids, respectively) and GLY-0Ac-1, GLY-0Ac-2 and GLY-0Ac. Negative control NC-1 (cells only) tested at a final concentration of 50 μg / ml of -3 (acetate-free dihydroxy fatty acid glycerides, C20, C21 and C22 fatty acids, respectively); 0.195 each. , 0.65 and 1.95 μg / ml test concentrations compared to positive controls PC-1, PC-2, PC-3 consisting of 5-FU; and PC-4 consisting of glycerol monopalmitate (MGP).

Results and Discussion This example shows that some of the glyceride compounds present in NZ propolis have novel anti-skin cancer activity against human melanoma cell line A-2508. The results of this bioassay are shown in Table 6. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 is considered;% inhibition is a percentage reduction in growth compared to negative controls, and large numbers indicate that the test compound has anticancer growth potential. show.

(Table 6) Antiproliferative activity of dihydroxy fatty acid glyceride against human melanoma cell line A-2508

All of the highly purified compounds inhibited the growth of human melanoma skin cancer cell lines by 72-92% when tested at 50 μg / ml. The most potent of these compounds was the non-acetylated dihydroxy fatty acid glyceride GLY-0Ac-2, which has a fatty acid chain length of 22 carbons. The antiproliferative activity of these dihydroxy fatty acid glycerides was superior to that of the positive control monoglycerol palmitate (MGP), which was also tested at 50 μg / ml. 5-Fluorouracil had low and non-significant activity at concentrations of 0.195, 0.65 and 1.95 μg / ml of the three tested.

Example 7: Antiproliferative activity of dihydroxy fatty acid glyceride against human epidermal cancer A-431 In this example, some of the glyceride compounds present in NZ propolis are novel against human epidermal cancer cell line A-431. Shows that it has anti-skin cancer activity. Glycerol test samples GLY-1Ac-1 (C20 dihydroxy fatty acid glyceride acetylated at the C3 position of glycerol) and GLY-0Ac-1 (C20 dihydroxy fatty acid glyceride without acetate on glycerol) of these, 50 μg / ml. Was tested for antiproliferative activity against human epidermal cancer cell line A-431 at the final concentration of. This cell proliferation assay was performed as described in Example 6. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC consisting of 5-FU at test concentrations of 0.195, 0.65 and 1.95 μg / ml, respectively. -2, PC-3; as well as PC-4 consisting of glycerol monopalmitate (MGP).

The results of this bioassay are shown in Table 7. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 7) Antiproliferative activity of dihydroxy fatty acid glyceride against human epidermal cancer cell line A-431

The two monoglyceride compounds tested, GLY-1Ac-1 and GLY-0Ac-1, have approximately the same level of growth inhibition at 80.6 and 81.5%, respectively, when tested at 50 μg / ml. This example shows that the number of acetates on glycerol is not significant with respect to activity. The antiproliferative activity of these dihydroxy fatty acid glycerides was similar to the positive control monoglycerol palmitate (MGP) also tested at 50 μg / ml. 5 Fluorouracil had low and non-significant activity at concentrations of 0.195, 0.65 and 1.95 μg / ml of the three tested.

Example 8: Human Basal Cell Carcinoma TE 354. Antiproliferative activity of dihydroxy fatty acid glyceride against T Glycerol test sample GLY-1Ac-1 (C20 dihydroxy fatty acid glyceride acetylated at the C3 position of glycerol) and GLY-0Ac-1 (C20 dihydroxy fatty acid glyceride without acetate on glycerol) ) Of these, human basal cell carcinoma cell line TE 345 at a final concentration of 50 μg / ml. It was tested for antiproliferative activity against T. This cell proliferation assay was performed as described in Example 6. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC consisting of 5-FU at test concentrations of 0.195, 0.65 and 1.95 μg / ml, respectively. -2, PC-3; as well as PC-4 consisting of glycerol monopalmitate.

In this example, some of the glyceride compounds present in NZ propolis are human basal cancer cell lines TE 354. It is shown to have a novel anti-skin cancer activity against T. The results of this bioassay are shown in Table 8. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 8) Antiproliferative activity of dihydroxy fatty acid glyceride against human basal cell carcinoma cell line TE354.T

The two monoglyceride compounds tested, GLY-1Ac-1 and GLY-0Ac-1, have similar levels of growth inhibition at 27.3 and 38.0%, respectively, when tested at 50 μg / ml. This example shows that zero acetate on glycerol improves biological activity against this skin cancer cell line. The antiproliferative activity of these dihydroxy fatty acid glycerides was superior to that of the positive control monoglycerol palmitate (MGP), which was also tested at 50 μg / ml. 5 Fluorouracil had low and non-significant activity at concentrations of 0.195, 0.65 and 1.95 μg / ml of the three tested.

Example 9: Antiproliferative activity of dihydroxy fatty acid glycerides and derivatives against human colon adenocarcinoma cell line DLD-1 In this example, the individual glycerides GLY-1Ac-1 and GLY-1Ac-2 (acetylated at the C3 position of glycerol). Dihydroxyfatty acid glycerides (C20 and C21 fatty acid chain lengths) and GLY-0Ac-1 and GLY-0Ac-2 (non-acetylated dihydroxyfatty acid glycerides, C20 and C21 fatty acid chain lengths) antiproliferative activity, colon adenocarcinoma cells It is shown that it was tested for antiproliferative activity at a final concentration of 50 μg / ml against strain DLD-1. GLY-1Ac-1 was also retested in the second assay at 50 and 25 μg / ml to show a dose response. This cell proliferation assay was performed as described in Examples 1 and 2. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive controls PC-1, PC-2 consisting of 5-FU at test concentrations of 0.65 and 1.95 μg / ml, respectively; and It was compared with PC-3 consisting of glycerol monopalmitate (MGP). Cell-only data NC-1 for the first bioassay trial and cell-only data NC-2 for the second bioassay trial were also included in the table.

This example shows that some of the glyceride compounds present in NZ propolis have novel anti-gastrointestinal cancer activity against the human colon adenocarcinoma cell line DLD-1. The results of this bioassay are shown in Table 9. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 9) Antiproliferative activity of dihydroxy fatty acid glyceride against human adenocarcinoma cell line DLD-1

Inhibition of growth of all monoglycerides with 0 or 1 acetate attached to glycerol ranged from 68 to 91% when tested at 50 μg / ml. The most potent of these compounds in the first assay was the monoacetylated dihydroxy fatty acid glyceride GLY-1Ac-2. The antiproliferative activity of these dihydroxy fatty acid glycerides was equal to or better than that of the positive control monoglycerol palmitate (MGP) also tested at 50 μg / ml. GLY-1Ac-1 was retested at 50 and 25 μg / ml. The LD50 of this compound is approximately 25-50 μg / ml, as the antiproliferative activity was 94% at 50 μg / ml but only 13% at 25 μg / ml. 5-Fluorouracil had low and non-significant activity at concentrations of 0.65 and 1.95 μg / ml of the two tested.

Example 10: Antiproliferative activity of dihydroxy fatty acid glyceride mixture, derivative and cyclodextrin complex against human adenocarcinoma cell line DLD-1 This example is a purified glyceride fraction GLY-conc; a purified glyceride derivative, For example, free fatty acids (FFA-conc), methyl esters (ME-conc) and peracetylated glycerides (PerAc-conc); and cyclodextrin complexes of glycerides g-CD GLY-conc (gamma-cyclodextrin-encapsulated glyceride concentrate) and It shows the antiproliferative activity of α-CD GLY-conc cyclodextrin complex (alpha-cyclodextrin-encapsulated glyceride concentrate) against human colon cancer cell line DLD-1. These fractions and samples were prepared as described in Examples 4 and 5 and tested for antiproliferative activity against colon adenocarcinoma cell line DLD-1 at the final effective concentration of 50 μg / ml glyceride concentrate. .. A cyclodextrin-encapsulated glyceride sample containing a 25% by weight glyceride concentrate was tested at a concentration of 200 μg / ml, which corresponds to 50 μg / ml glyceride. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC- consisting of 5-FU at test concentrations of 6.5, 19.5 and 58.5 μg / ml. 2, PC-3; as well as PC-4 consisting of glycerol monopalmitate. The results of this bioassay are shown in Table 10. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 10) Antiproliferative activity of dihydroxy fatty acid glyceride concentrates, derivatives and complexes against human colon adenocarcinoma cell line DLD-1

In this example, a glyceride mixture isolated from NZ Propolis; derivatives of glycerides such as free fatty acids, alkyl esters and peracetates; and cyclodextrin-encapsulated glycerides are novel anti-human colon adenocarcinoma cell lines DLD-1. Shows that it has gastrointestinal cancer activity. The most potent of these test substances (82% inhibition of growth) is the monoglyceride concentrate. The most potent of these derivatives and complexes was the 47% inhibitory methyl ester, followed by 33 and 28% alpha cyclodextrin and gamma cyclodextrin complexes, respectively. The peracetate and free fatty acid had the lowest antiproliferative activity of 19 and 10%, respectively. The test concentrations of these derivatives may have been too low. 5-Fluorouracil had low and non-significant activity at the tested concentrations of 6.5, 19.5 and 58.5 μg / ml.

Example 11: Antiproliferative activity of dihydroxy fatty acid glyceride against human gastric cancer cell line NCI-N87 This example shows the individual glycerides GLY-1Ac-1 and GLY-1Ac-2 (dihydroxy fatty acid acetylated at the C3 position of glycerol). Glyde, C20, C21, C22 fatty acid chain length), GLY-0Ac-1, GLY-0Ac-2, GLY-0Ac-3 (non-acetylated dihydroxy fatty acid glyceride, C20, C21, C22 fatty acid chain length) and GLY-2Ac The antiproliferative activity of -1 mix (dihydroxy fatty acid glycerides acetylated at the C2 and C3 positions on glycerol, a mixture of multiple dihydroxy fatty acid chain lengths) was measured at a final concentration of 50 μg / ml against the human gastric cancer cell line NCI-N87. It is shown that it was tested for antiproliferative activity in. GLY-1Ac-1 was also tested at 25 and 10 μg / ml and showed a dose response. This cell proliferation assay was performed as described in Examples 1 and 2. Negative control NC-1 (cells only) tested from this test sample at 50 μg / ml; positive control PC-1, PC consisting of 5-FU at test concentrations of 6.5, 19.5 and 58.5 μg / ml. -2, PC-3; as well as PC-4 consisting of glycerol monopalmitate (MGP). The results of this bioassay are shown in Table 11. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 is considered;% inhibition is a percentage reduction in growth compared to negative controls, and large numbers indicate that the test compound has anticancer growth potential. show.

(Table 11) Antiproliferative activity of dihydroxy fatty acid glyceride against human gastric cancer cell line NCI-N87

This example shows that some of the glyceride compounds present in NZ propolis have novel and highly potent anti-gastrointestinal cancer activity against the human gastric cancer cell line NCI-N87. All isolated non-acetate and monoacetate compounds were cytotoxic (100% inhibition of growth) when tested at 50 μg / ml. The mixture of diacetate glyceride compounds, the GLY-2Ac-1 mix, was strongly antiproliferative but 52% inhibitory and not cytotoxic. The reduction of the test concentration of the monoacetate compound GLY-1Ac-1 from 50 μg / ml to 25 μg / ml reduced the antiproliferative activity to 86% (still very strong activity). Further reduction of the test concentration from 25 μg / ml to 10 μg / ml reduced antiproliferative activity to 39%. Therefore, the LD50 is approximately 25-10 μg / ml. 5-Fluorouracil had low and non-significant activity at the tested concentrations of 6.5, 19.5 and 58.5 μg / ml, with the highest activity obtained at 6.5 μg / ml. Glycerol monopalmitate (MGP) was also cytotoxic at test concentrations of 50 μg / ml.

Example 12: Antiproliferative activity of dihydroxy fatty acid glyceride mixture, derivative and cyclodextrin complex against human gastric cancer cell line NCI-N87 This example is a purified glyceride fraction GLY-conc; a purified glyceride derivative, eg. Free fatty acids (FFA-conc), methyl esters (ME-conc) and peracetylated glycerides (PerAc-conc); and cyclodextrin complex of glycerides g-CD GLY-conc (gamma-cyclodextrin-encapsulated glyceride concentrate) and α -It shows the antiproliferative activity of the cyclodextrin complex (alpha-cyclodextrin-encapsulated glyceride concentrate) of CD GLY-conc against the human gastric cancer cell line NCI-N87. These fractions and samples were prepared as described in Examples 4 and 5 and tested for antiproliferative activity against the gastric cancer cell line NCI-N87 at the final effective concentration of 50 μg / ml glyceride concentrate. Cyclodextrin-encapsulated glyceride samples containing 25% by weight glyceride concentrate were tested at a concentration of 200 μg / ml, which corresponds to 50 μg / ml glyceride. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC- consisting of 5-FU at test concentrations of 6.5, 19.5 and 58.5 μg / ml. 2, PC-3; as well as PC-4 consisting of glycerol monopalmitate (MGP). The results of this bioassay are shown in Table 12. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 12) Antiproliferative activity of dihydroxy fatty acid glyceride concentrate, derivative and complex against human gastric cancer cell line NCI-N87

In this example, a glyceride mixture isolated from NZ propolis; derivatives such as free fatty acids, alkyl esters and peracetates; and cyclodextrin-encapsulated glycerides are novel anti-gastrointestinal cancer activity against the human gastric cancer cell line NCI-N87. Indicates that it has. The most potent of these test substances (82% inhibition of growth) is the monoglyceride concentrate. The most potent of these derivatives and complexes are 70% inhibitory methyl ester, 78% beta-cyclodextrin complex, 68% alpha cyclodextrin complex and 65% gamma cyclodextrin complex, respectively. rice field. The peracetates and free fatty acids had lower but still strong antiproliferative activity of 60 and 55%, respectively. 5-Fluorouracil had low and non-significant activity at the tested concentrations of 6.5, 19.5 and 58.5 μg / ml, with the highest activity obtained at 6.5 μg / ml. Glycerol monopalmitate (MGP) was cytotoxic at test concentrations of 50 μg / ml.

Example 13: Antiproliferative activity of dihydroxy fatty acid glycerides against human esophageal cancer cell line KYSE-30 This example shows the individual glycerides GLY-1Ac-1 and GLY-1Ac-2 (dihydroxy acetylated at the C3 position of glycerol). Fatty acid glycerides (C20, C21 fatty acid chain lengths, respectively), GLY-0Ac-1, GLY-0Ac-2, GLY-0Ac-3 (non-acetylated dihydroxy fatty acid glycerides, C20, C21, C22 fatty acid chain lengths, respectively) and GLY- The antiproliferative activity of the 2Ac-1 mix (dihydroxy fatty acid glycerides acetylated at the C2 and C3 positions of glycerol, a mixture of multiple fatty acid chain lengths) was measured at a final concentration of 50 μg / ml against the human esophageal cancer cell line KYSE-30. It is shown that it was tested for antiproliferative activity in. GLY-1Ac-1 was also tested at 25 and 10 μg / ml to show a dose response. This cell proliferation assay was performed as described in Examples 1 and 2. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC- consisting of 5-FU at test concentrations of 6.5, 19.5 and 58.5 μg / ml. 2, PC-3; as well as PC-4 consisting of glycerol monopalmitate (MGP). The results of this bioassay are shown in Table 13. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value (NS = not significant); p is the measured value is student. Probability values that are statistically significant by t-test, where <0.05 is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, large numbers are anti-test compounds. Shows that it has the ability to grow cancer.

(Table 13) Antiproliferative activity of dihydroxy fatty acid glyceride against human esophageal cancer cell line KYSE-30

This example shows that some of the glyceride compounds present in NZ propolis have novel and potent anti-gastrointestinal cancer activity against the human esophageal cancer cell line KYSE-30. All isolated non-acetate and monoacetate compounds had moderate to strong antiproliferative properties (34-86%) when tested at 50 μg / ml, with GLY-1Ac-1 being the most potent. .. A mixture of diacetate glyceride compounds, the GLY-2Ac-1 mix, was 25% inhibitory and moderately antiproliferative. Decreasing the test concentration of the monoacetate compound GLY-1Ac-1 from 50 μg / ml to 25 μg / ml reduced the antiproliferative activity to 50% (still strong activity). Further reduction of the test concentration from 25 μg / ml to 10 μg / ml reduced antiproliferative activity to a statistically non-significant level of 9%. Therefore, the LD50 is approximately 25 μg / ml. 5-Fluorouracil had a low but significant activity of 17% when tested at 58.5 μg / ml, but not at lower concentrations of 6.5 and 19.5 μg / ml. Glycerol monopalmitate (MGP) had a strong antiproliferative activity of 75% when tested at 50 μg / ml.

Example 14: Antiproliferative activity of dihydroxy fatty acid glyceride mixture and derivative against human esophageal squamous cell carcinoma cell line KYSE-30 This example is a purified glyceride fraction GLY-conc; a purified glyceride derivative, eg, free fatty acid. (FFA-conc), methyl ester (ME-conc) and peracetylated glyceride (PerAc-conc) show antiproliferative activity against the human esophageal squamous cell carcinoma cell line KYSE-30. These fractions and samples were prepared as described in Examples 4 and 5 and tested for antiproliferative activity at the final effective concentration of 50 μg / ml glyceride concentrate against esophageal squamous cell carcinoma cell line KYSE-30. .. Negative control NC-1 (cells only) tested with test samples at 50 μg / ml; positive control PC-1, PC- consisting of 5-FU at test concentrations of 6.5, 19.5 and 58.5 μg / ml. 2, PC-3; as well as PC-4 consisting of glycerol monopalmitate (MGP). The results of this bioassay are shown in Table 14. In this table, OD is the optical density measured at 570 nm; SEM is the standard error of the measured value associated with the measured average optical density value; p is the measured value statistically by Student's t-test. A significant probability value, where <0.05 (NS = not significant) is considered;% inhibition is a percentage reduction in proliferation compared to negative controls, with higher numbers being anti-test compounds. Shows that it has the ability to grow cancer.

(Table 14) Antiproliferative activity of dihydroxy fatty acid glyceride concentrate and derivative against human esophageal squamous cell carcinoma cell line KYSE-30

This example is a glyceride mixture isolated from NZ propolis; derivatives such as free fatty acids, alkyl esters and peracetates have novel anti-gastrointestinal cancer activity against the human esophageal squamous cell carcinoma cell line KYSE-30. Is shown. The most potent (44% inhibition of growth) of these test substances is the monoglyceride concentrate. The most potent of these derivatives was the 32% inhibitory peracetate. Methyl esters and free fatty acids had slightly lower antiproliferative activity of 28 and 21%, respectively. 5-Fluorouracil had a low but significant activity of 16.8% inhibition at the tested concentrations of 58.5 μg / ml, but not significant activity at the lower concentrations of 6.5 and 19.5 μg / ml. .. Glycerol monopalmitate (MGP) had a strong antiproliferative activity of 75% when tested at 50 μg / ml.

Example 15: Isolation of dihydroxyfatty acid glycerides from poplar trees In this example, certain species or hybrids of poplar are sources of dihydroxyfatty acid glycerides found in New Zealand propolis, and thus propolis or chemical synthesis. Shows that it is an alternative plant source of this glyceride to.

Samples of poplar buds, twigs and leaves are collected from September-February from the Plant and Food Research poplar collection at Aokaoutere (Manawatu, New Zealand) and from the Akura Conservation Center (Masterton) did. Most of the samples were from thickets, so these samples were easily accessible.

The sample was weighed and extracted with absolute ethanol at room temperature for about 2 hours. This sample was extracted as is without soaking or slicing. Each sample was prepared for LC-MS analysis by drying the extract, weighing it and making an ethanol solution at 5 mg / ml. For comparative analysis, leaf and flower material samples were taken from two Paulownia tomentosa trees and samples were taken from the leaves and buds of mature willow trees at Hut Valley. The material was extracted by immersing this plant material in ethyl acetate, and the waxy outer layer of this material alone was extracted.

All samples were analyzed using the LC-MS method developed for glycerides present in propolis as described in Example 4. This method of analysis, along with other glycerides (if any), could detect novel dihydroxy fatty acid glycerides at very low levels.

Results Table 15 shows the qualitative levels of dihydroxyfatty acid glycerides in leaves or buds in the twigs of various poplar species.

np= グリセリドは存在せず、++ 中レベルのグリセリド、+++ 高レベルのグリセリド、ND= 未測定 (Table 15) Qualitative glyceride content in New Zealand poplar varieties

np = no glycerides, ++ medium levels of glycerides, +++ high levels of glycerides, ND = unmeasured

This analysis showed that the same dihydroxyfatty acid glycerides found in propolis were present in many of the more commonly planted New Zealand poplar cultivars analyzed. This glyceride was found in many poplar leaves, twigs and buds and appeared to be generally associated with resin at these sites.

The fatty acid profile of this glyceride is similar to that found in propolis, suggesting that poplar is a source of propolis glyceride. It is expected that the individual glycerides could be isolated from the poplar exudate in a manner similar to that used in Example 4. Cultivated varieties of poplar (eg, "Tasman" and "Fraser") are representative of the widely planted Poplar x Euramalica (also known as Canadian poplar and Carolina poplar). However, Popls deltoides x nigra hybrids (eg, Selwyn) are also common in New Zealand. Dihydroxy fatty acid glycerides have usually been found to be absent in some of the other cultivars (eg, P. maximowiczii x nigra clones and Chinese poplar species "Yunan"). .. Glycetes were not present in hybrids that did not contain crossbreeds with Deltoides. These types of glycerides were also not present in willow leaf and sprout samples, but in Paulownia various types of glycerides are present at low levels, which is the reason for these plants. It is shown that the species is not a source of glyceride in propolis and is not a suitable plant species for the isolation of the glyceride compounds described herein.

Example 16: Determining the Chirality of Novel Glycoides This example shows that naturally occurring novel dihydroxyfatty acid glycerides have 3R, 8R stereochemistry. Chiral analysis of alcohol groups of organic molecules is generally performed using chiral derivatization reagents. This reagent is available in R and S forms and usually contains aromatic groups that, when attached to alcohol groups, can affect the 1H NMR chemical shift of adjacent groups by blocking. Changes in the shift of adjacent groups with respect to the separately prepared R and S derivatives indicate the chirality of the original alcohol. For this novel glyceride, the stereochemistry of the alcohol groups of 3,8-dihydroxy fatty acids is of most interest. Since the length of this fatty acid chain is not affected by the chemical shift of protons at positions C-2, C-3 and C-8, a crude glyceride mixture was used for this study.

Preparation of R, S Diesters and 1H-NMR Analysis This crude glyceride mixture was hydrolyzed using LiOH as described in Example 4. The free fatty chain methyl ester was then prepared using diazomethane from the hydrolyzed glyceride mixture described in Example 4. R- and S-α-methoxyphenylacetic acid (MPA), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) were purchased from Sigma. The chiral ester derivatization method used was that described in Freire et al. 2005. 10 mg of the dihydroxy free fatty acid methyl ester mixture was dissolved in about 0.8 mL of CH ₂ Cl ₂ (dry) in a 5 mL reaction vial. The solution was stirred using a magnetic stirrer at room temperature and 23 mg of R-α-methoxyphenylacetic acid, 10 μL of EDC and a catalytic amount of DMAP were added. The reaction was completed by washing the reaction solution with water, 1M HCl, sodium bicarbonate and water. The organic layer was dried under vacuum and purified using a small silica gel column to give the diester product (about 8 mg). S-diesters were obtained as well. A 1H NMR sample was dissolved in CDCl ₃ and run at 500 MHz. The product was then examined by 1 H NMR.

Results and Discussion Signals for H-2, H-3 and H-8 were well separated for detailed analysis. The first observation was that the two products were single species by NMR. This will only be true if the original alcohol is chiral (ie, the C-3 and C-8 hydroxyls are stereospecific and are either R or S, respectively). The shift changes Δδ (SR) of these derivatives are shown in Table 16. Based on comparisons with similar compounds in the literature (Tables 17 and 18), this result shows that the stereochemical arrangement is 3R, 8R for all glycerides.

(Table 16) 1H NMR chemical shift differences between R MPA and S MPA esters for 3,8 dihydroxy fatty acid methyl esters

Confirmation of stereochemistry by comparison with the literature Then, the change in the shift of Δδ (SR) can be compared with the related example from the literature to confirm the stereochemistry. The literature describes two examples for which direct comparison is effective and similar derivatizing agents are used, such as 3,7-diacetoxydokosahexanoic acid (also known as birsonic acid). ) (Reis et al. 2007) and 1-acetyl-2- (3,7-diacetoxyeiconsaonyl) -glycerol (1-acetyl-2- (3,7-diacetoxyeconsaonyl) -glycerol) (also known as). It is also known as oncidinol (also known as Reis et al. 2003). Bison acid was hydrolyzed to remove acetoxy groups to produce 3,7 dihydroxy fatty acids. The chiral derivatizing agent Mosheric acid (methoxy {trifluoromethyl} phenylacetic acid) was then used to prepare 3,7 diesters, which were then examined by 1H NMR. The changes in Δδ (SR) are shown in Table 17, which allows Reis et al. 2007 to assign this acid to (3R, 7R) -3,7-dihydroxydokosanoic acid.

(Table 17) 1H NMR chemical shift difference between R Mosher ester and S Mosher ester for 3,7 dihydroxy fatty acid methyl ester derived from bisonic acid

Similarly, Reis et al. 2003 also hydrolyzed oncidinol to remove glycerol and acetoxy groups to give 3,7 dihydroxy fatty acids, which were derivatized into diesters using moscher acid, the 3, The 7 diesters were examined by 1H NMR. The changes in Δδ (SR) shown in Table 18 made it possible to assign this acid to the 3R, 7R dihydroxyic acid.

(Table 18) 1H NMR chemical shift difference between R Mosher ester and S Mosher ester for 3,7 dihydroxy fatty acid methyl ester derived from oncidinol

For both bisonic acid and oncidinol, the results are very similar to those seen for the novel glycerides in Table 16. The Δδ (SR) value is negative for H-2 and H-3 and positive for the distant hydroxy position H8, confirming that the stereochemical arrangement is 3R, 8R for all glycerides. do.
Freere F, Seco JM, Quinoa E, Riguara R.M. The prediction of the absolute stereochemistry of primitive and secondary 1,2-diols by 1H NMR spectroscopy: principaliples and applications. Chemistry 2005 19; 11 (19): 5509-22).
Reis, M. et al. G. , De Faria, A. D. , Dos Santos, I. A. , Amaral, M. et al. D. C. E. , Marsaioli, A.M. J. Byrsonic acid-The blue to floral mimicry involving oil-producing flowers and oil-collecting bees. Journal of Chemical Ecology. 2007, 33 (7), pp. 1421-1249
Reis, M. et al. G. , De Faria, A. D. , Do Amaral, M.D. D. C. E. , Marsaioli, A.M. J. Oncidinol-A novel diglyceride cerol from Ornithophora radicals Barb. Rodr. (Orchidaceae) floral oil. 2003. Tetrahedron Letters. 44 (46), pp. 8519-8523

Industrial availability The antiepithelial cancer composition of the present invention (eg, a compound-rich propolis of formula (I) or an extract or fraction thereof containing cyclodextrin, and a propolis or a fraction thereof are derived. Isolated or purified compounds are included in the pharmaceutical and medical fields (eg medical devices, medical supplies and pharmaceuticals) and consumer goods (eg foods and beverages, compositions, functional foods, functional cosmetics and Can be used in functional foods). For example, methods of using such compositions in the treatment of epithelial cancers (eg skin cancers) and their symptoms are applicable in the medical field.

Claims (17)

A pharmaceutical composition for treating or preventing a subject's epithelial cancer, or a pharmaceutical composition for inducing apoptosis of one or more neoplastic epithelial cells of a subject, according to the formula ( I) Containing an effective amount of one or more compounds of I) or a pharmaceutically acceptable salt or admixture thereof of one or more thereof.

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Pharmaceutical composition. Containing therapeutically effective amounts of the compound of formula (I),

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Pharmaceutical composition. The pharmaceutical composition according to claim 1 or 2, wherein R ₆ is H. The pharmaceutical composition according to claim 1 or 2, wherein R ₆ is CH ₃ . (A) 3,8-Dihydroxyeicosanoic acid,
(B) 1- (3,8-dihydroxyeicosanoyl) glycerol,
(C) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
(D) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
(E) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
(F) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
(G) 3,8-Dihydroxyeicosanoic acid methyl ester,
(H) 3,8-Dihydroxyheneicosanoic acid,
(I) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
(J) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
(K) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
(L) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
(M) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
(N) 3,8-Dihydroxyheneicosanoic acid methyl ester,
(O) 3,8-dihydroxydokosanoic acid,
(P) 1- (3,8-dihydroxydocosanoyl) glycerol,
(Q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
(R) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
(S) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
(T) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and (u) 3,8-dihydroxydokosanoic acid methyl ester or any one of the pharmaceuticals (a) to (u). Any one of claims 1-3, comprising a therapeutically effective amount of at least one compound of formula (I) selected from any one or more of the acceptable salts or solvates. The pharmaceutical composition according to. The use of the compound of formula (I),

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Inhibition of subject epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer; in induction of apoptosis of one or more neoplastic epithelial cells of subject; epithelial cancer Increasing the subject's responsiveness to treatment; in increasing the sensitivity of the subject's epithelial tumor to the treatment of epithelial cancer; By at least a partial reversal of the resistance of the neoplastic cells of the subject suffering from epithelial cancer to the treatment of epithelial cancer; by the complete reversal of the resistance of the patient suffering from the epithelial cancer to the treatment of epithelial cancer. Or in a partial reversal; or one or more of patients suffering from epithelial cancer who are or are expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment. Use in the manufacture of compositions for use in increasing the susceptibility of species tumors to treatment with epithelial cancer treatment. The use according to claim 6, wherein the subject is a human subject. The use according to claim 6 or 7, wherein the compound is the compound defined in any one of claims 2, 3 or 4. (A) 3,8-Dihydroxyeicosanoic acid,
(B) 1- (3,8-dihydroxyeicosanoyl) glycerol,
(C) 1- (3,8-dihydroxyeicosanoyl) 2-acetoxyglycerol,
(D) 1- (3,8-dihydroxyeicosanoyl) 3-acetoxyglycerol,
(E) 1- (3,8-dihydroxyeicosanoyl) 2,3-diacetoxyglycerol,
(F) 1- (3,8-diacetoxyeicosanoyl) 2,3-diacetoxyglycerol,
(G) 3,8-Dihydroxyeicosanoic acid methyl ester,
(H) 3,8-Dihydroxyheneicosanoic acid,
(I) 1- (3,8-dihydroxyheneicosanoyl) glycerol,
(J) 1- (3,8-dihydroxyheneicosanoyl) 2-acetoxyglycerol,
(K) 1- (3,8-dihydroxyheneicosanoyl) 3-acetoxyglycerol,
(L) 1- (3,8-dihydroxyheneicosanoyl) 2,3-diacetoxyglycerol,
(M) 1- (3,8-diacetoxyheneicosanoyl) 2,3-diacetoxyglycerol,
(N) 3,8-Dihydroxyheneicosanoic acid methyl ester,
(O) 3,8-dihydroxydokosanoic acid,
(P) 1- (3,8-dihydroxydocosanoyl) glycerol,
(Q) 1- (3,8-dihydroxydocosanoyl) 2-acetoxyglycerol,
(R) 1- (3,8-dihydroxydocosanoyl) 3-acetoxyglycerol,
(S) 1- (3,8-dihydroxydocosanoyl) 2,3-diacetoxyglycerol,
(T) 1- (3,8-diacetoxydokosanoyl) 2,3-diacetoxyglycerol and (u) 3,8-dihydroxydokosanoic acid methyl ester or any one of (a) to (u) pharmaceuticals. Use of at least one compound selected from any one or more of the group consisting of qualifyingly acceptable salts or solvates, optionally in combination with at least one additional therapeutic agent.
Inhibition of subject epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer; in induction of apoptosis of one or more neoplastic epithelial cells of subject; epithelial cancer Increasing the subject's responsiveness to treatment; in increasing the sensitivity of the subject's epithelial tumor to the treatment of epithelial cancer; By at least a partial reversal of the resistance of the neoplastic cells of the subject suffering from epithelial cancer to the treatment of epithelial cancer; by the complete reversal of the resistance of the patient suffering from the epithelial cancer to the treatment of epithelial cancer. Or in a partial reversal; or one or more of patients suffering from epithelial cancer who are or are expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment. Use in the manufacture of compositions for use in increasing the susceptibility of species tumors to treatment with epithelial cancer treatment. Inhibition of epithelial tumor formation, inhibition of epithelial tumor growth, inhibition of epithelial tumor metastasis or treatment or prevention of epithelial cancer in human subjects; in induction of apoptosis of one or more neoplastic epithelial cells in human subjects; One or more epithelial cancers in human subjects that are resistant to treatment; in increased responsiveness of human subjects to treatment of epithelial cancer; in increased sensitivity of epithelial tumors in human subjects to treatment of epithelial cancer; By increasing the sensitivity of the cells; with at least a partial reversal of resistance to epithelial cancer treatment of neoplastic cells in human subjects suffering from epithelial cancer; epithelium of human patients suffering from epithelial cancer. Suffering from epithelial cancer, with complete or partial reversal of resistance to cancer treatment; or with or expected to be resistant or expected to be resistant to treatment with epithelial cancer treatment The pharmaceutical composition according to any one of claims 2 to 5, for use in increasing the susceptibility of one or more tumors of a human patient to treatment with epithelial cancer treatment. The pharmaceutical composition according to claim 10, for use in the treatment or prevention of epithelial cancer. A method of isolating or purifying a compound of formula (I) or a mixture of compounds of formula (I) from propolis or poplar or an extract or exudate thereof.
(A) Preparation of poplar extract, poplar-derived propolis or extracts or exudates thereof, and (b) Isolation or purification of the compound from the poplar, propolis or extracts or exudates thereof. Including methods. Poplar extract, poplar-derived propolis or an extract or exudate thereof comprises Populus deltoides, its cultivated varieties, hybrids and hybrids, Populus deltoides x nigra or Populus Euramelicana. 12. The method of claim 12, which is derived from a hybrid of Populus del Toides, including Populus euramericana Guinier. 13. The method of claim 13, wherein the popls Euramericana ginier is a cultivar selected from the group Selwyn, Tasman, Luisa Avanzo and Fraser. (A) The poplar, propolis or an extract or exudate thereof is fractionated by chromatography and / or solvent splitting and / or supercritical extraction to one of the compounds of formula (I) or The process of obtaining one or more fractions containing multiple species,
(B) The poplar, propolis or an extract or exudate thereof or one or more fractions are fractionated by preparative HPLC and / or polymer resin fraction, among the compounds of formula (I). The step of obtaining one or more fractions comprising one or more, and optionally (c) one or more compounds of formula (I) further from the one or more fractions of step (a). 12-. The method according to any one of 14. 15. The method of claim 15, wherein the chromatography is column chromatography, reverse phase chromatography, normal phase chromatography, or supercritical liquid chromatography. A composition or product comprising one or more compounds of formula (I).
The amount and / or concentration of one or more compounds of formula (I) is specified on the label associated with the composition or product.

In formula (I),
R ₂ , R ₃ , R ₄ and R ₅ are independently H or acetyl (CH ₃ CO-), respectively.
R ₆ is H or CH ₃ and R ₇ is a saturated or unsaturated hydrocarbon of CH ₃ or C2-C6.
x and y are independently integers of 3 to 14, respectively.
However, when R ₆ is H, x + y is more than 10 and 18 or less, and when R ₆ is CH ₃ , x + y is more than 9 and 17 or less.
Composition or product.