WO2012036180A1 - Xanthone derivative and use thereof - Google Patents
Xanthone derivative and use thereof Download PDFInfo
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- WO2012036180A1 WO2012036180A1 PCT/JP2011/070922 JP2011070922W WO2012036180A1 WO 2012036180 A1 WO2012036180 A1 WO 2012036180A1 JP 2011070922 W JP2011070922 W JP 2011070922W WO 2012036180 A1 WO2012036180 A1 WO 2012036180A1
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- 0 CC(C)=CCc(c(O)c(c(Oc(c1c2CC=C(C)C)cc(O*)c2OC)c2)C1=O)c2O* Chemical compound CC(C)=CCc(c(O)c(c(Oc(c1c2CC=C(C)C)cc(O*)c2OC)c2)C1=O)c2O* 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
- C07D311/86—Oxygen atoms, e.g. xanthones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- the present invention relates to xanthone derivatives and uses thereof, and more particularly to ⁇ -mangostin C 8-14 medium chain fatty acid diesters having excellent pharmaceutical action and uses thereof.
- Mangosteen (scientific name: Garcinia mangostana L) is an evergreen small Takagi of Guttiferae native to Southeast Asia.
- the fruit is one of the three largest fruits in the world, called the fruit queen, and is a high-class tropical fruit that represents Southeast Asia.
- the size of the fruit is about 5cm in size and has a thick skin.
- the pulp is white and is divided like a mandarin orange bag.
- the pericarp contains yellow pigments (xanthones) and has long been used as an astringent such as hemostatic, analgesic, antiseptic and anti-inflammatory, and is an important natural resource as a folklore drug.
- the main components of xanthone derivatives contained in mangosteen peel are ⁇ -mangostin and ⁇ -mangostin.
- Non-patent document 1 anti-MRSA (mesitillin-resistant Staphylococcus aureus) activity
- Non-patent document 2 histamine and serotonin receptor inhibitory activity
- Non-patent document 3 antioxidant activity
- Non-patent document 4 antiallergic activity
- various physiological activities such as apoptosis-inducing ability against cancer cells (non-patent document 5), cell cycle arrest (non-patent document 6), and various effects of mangosteen are explained by them.
- Non-patent Documents 7 and 8 NK activity is increased in mice and humans administered with ⁇ -mangostin or ⁇ -mangostin.
- panaxanthone a mixture of ⁇ -mangostin 75 to 85% and ⁇ -mangostin 5 to 15%, and the total content of both is 90% or more
- ⁇ -mangostin was administered to mouse breast cancer using an osmotic pump at a dose of 20 mg / kg, prolonged survival and suppression of lymph node metastasis were observed.
- Non-Patent Documents 10 and 11 have been reported.
- the terminal image of cancer is death due to metastasis. Even in breast cancer, most of the causes of death are due to metastasis to lymph nodes, lungs, etc., and suppressing metastasis is the biggest problem in cancer treatment.
- ⁇ -mangostin for example, ⁇ -mangosteen triacetate is known, and this compound is said to have an action of improving the aesthetic appearance of the skin and a therapeutic action against telangiectasia (patent). Reference 1).
- An object of the present invention is to provide an ⁇ -mangostin derivative having a more excellent anticancer activity and cancer metastasis suppressing activity.
- C8-14 medium chain fatty acid diester of ⁇ -mangostin has significantly superior anticancer activity and cancer metastasis inhibitory activity compared to ⁇ -mangostin.
- the present invention has been completed.
- R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.
- ⁇ -mangosteen dodecanoic acid diester represented by (7)
- the ⁇ -mangostin diester (1) according to the present invention is useful as an anticancer agent or cancer metastasis inhibitor since it has an excellent anticancer activity and cancer metastasis inhibitory activity.
- the diagram which shows the time-dependent change (per animal) of the body weight of the mouse
- FIG. 3 is a diagram showing changes in tumor volume over time (per mouse) of mice treated with ⁇ -mangosteen dodecanoic acid diester-containing diet. The photograph which shows the bioluminescence imaging of 6-week progress of the mouse
- the compound of the present invention has the general formula (1):
- R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.
- R 1 is a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.
- Nonanoic acid (C 9 ) pelargonic acid
- decanoic acid (C 10 ) capric acid
- dodecanoic acid (C 12 ) lauric acid
- saturated or unsaturated medium chain fatty acids having 8 to 12 carbon atoms are more preferable
- saturated medium chain fatty acids having 10 to 12 carbon atoms are particularly preferable.
- these two ester bonds are formed by combining C 8-14 medium chain fatty acids with hydroxyl groups at the 3rd and 6th positions of the xanthone skeleton.
- ⁇ -mangosteen octanoic acid diester ⁇ -mangosteen decanoic acid diester, ⁇ -mangosteen dodecanoic acid diester and ⁇ -mangostin 10-undecenoic acid diester are preferable, and ⁇ -mangosteen dodecanoic acid diester is particularly preferable.
- ⁇ -mangosteen dodecanoic acid diester is also represented by the chemical name of 1,3,6-trihydroxy-7-methoxy-2,8-di (3-methyl-2-butenyl) xanthone and 3,6-O-didodecanoate. The structural formula is as follows.
- the ⁇ -mangosteen diester (1) of the present invention has the following formula:
- R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.
- R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.
- Examples of the reactive derivative at the carboxyl group of the compound represented by the general formula (2) include acid halides, acid anhydrides, activated amides, activated esters and the like obtained according to a conventional method.
- Suitable examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl Phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid and other aliphatic carboxylic acids, or Mixed anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetrical an
- the esterification reaction is usually water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and pyridine.
- the reaction can be performed in any other organic solvent as long as it is performed in a solvent but does not adversely affect the reaction. These common solvents may be used as a mixture with water.
- the compound of the general formula (2) is used in the form of a free acid or a salt thereof, for example, N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′ -(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2 -Methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphit
- a method using a condensing agent such as N, N′-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole or N-hydroxy-5-norbornene-endo-2,3-dicarboximide is also desirable.
- the reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonates tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. You may go.
- the use ratio of ⁇ -mangostin as a raw material to the compound of the general formula (2) or a reactive derivative thereof in the carboxyl group is usually 2 mol or more, preferably 5 to 50 mol, with respect to 1 mol of the former.
- the reaction temperature is not critical, but the reaction is usually carried out under cooling to warming (-10 to 120 ° C.).
- the reaction time is usually about 0.5 hour to about 10 hours, preferably about 1 hour to about 5 hours.
- the ⁇ -mangosteen diester (1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent distillation, crystallization, transfer dissolution, chromatography and the like.
- Raw material compound (2) can be produced, for example, by the method described in Phytochemistry 1995, 39, 943-944.
- the ⁇ -mangosteen diester (1) thus obtained (hereinafter appropriately referred to as compound (1)) has excellent anticancer activity and cancer metastasis inhibitory activity, and is therefore used as an anticancer agent or cancer metastasis inhibitor. be able to.
- the target cancer is not particularly limited, and various cancers (for example, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma)
- cancers for example, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma
- the compound (1) of the present invention is used not only for humans but also for mammals other than humans (for example, horses, cows, dogs, cats, pigs, monkeys, etc.). can do.
- the compound (1) of the present invention When used as an anticancer agent or cancer metastasis inhibitor, it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, etc., and tablets, capsules, It can be formulated into granules, powders, syrups, etc. and administered orally, or can be formulated into intravenous injections, intramuscular injections, etc. and administered parenterally.
- excipients eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, carboxymethyl starch; crystalline cellulose -Cellulose derivatives such as low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic Dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfates such as calcium sulfate Conductors, etc.), binders (for example, the aforementioned excipients; gelatin; polyvinylpyrrolidone; maglogol, etc.), disintegrants (for example, the aforementioned excipients; gelatin;
- the dose of the compound (1) of the present invention varies depending on the age, body weight, symptoms, etc., and the administration form and the number of administrations, but is usually 1 to 2000 mg per day for an adult (body weight 50 kg), particularly About 10 to 500 mg is preferably administered once or divided into several times.
- the compound (1) of the present invention can be used in combination with other anticancer agents or cancer metastasis inhibitors.
- the concomitant agent include adriamycin, mitomycin, 5-fluorouracil, irinotecan, taxol and the like.
- the administration timing of each drug is not limited, and may be administered simultaneously or with a time difference.
- the compounding ratio of the compound (1) of the present invention to the drug used in combination can be appropriately selected according to the administration subject, administration route, target disease, symptom, combination and the like.
- the breast cancer cell line BJMC3879Luc2 used in this experiment is one in which a luciferase gene is stably integrated into a BJMC3879 cell line established from breast cancer induced by inoculating BALB / c mice with MMTV (mouse breast cancer virus). Yes (see Anticancer Res 29: 4389-4396, 2009). Transplanting the BJMC3879 cell line into syngeneic mice causes a high rate of metastasis to lymph nodes and lungs (Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25: 1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007).
- BJMC3879Luc2 cells (2.5 ⁇ 10 6 cells / 0.3 ml) were transplanted subcutaneously into the groin area of 6-week-old BALB / c female mice (Japan SLC), resulting in a tumor diameter of 0.3 to 0.4 cm.
- ⁇ -mangosteen dodecanoic acid diester-containing diet (0 ppm [control group], 2000 ppm and 4000 ppm) was freely given to 10 mice in each group (30 mice in total) for 6 weeks.
- Ten mice in each group were housed in two cages in groups of five. Weekly, food intake was measured for each cage, and body weight and mammary tumor size were measured for each individual.
- survival rate The survival rate is as shown in FIG. As is apparent from this figure, 5 death cases (5/10) were observed at the 6th and 7th week in the control group, whereas one case at 7th week in the feed administration group containing the specimen 2000 ppm. Only death cases (1/10) were observed, and no death cases were observed in the 4000 ppm feed administration group (0/10). That is, the survival rate at the end of the experiment is 50% in the control group, 90% in the feed administration group containing 2000 ppm, 100% in the feed administration group containing 4000 ppm, and statistically between the control group and the feed administration group containing 4000 ppm. Differences were observed.
- Tumor Volume The change in tumor volume over time is as shown in FIG. As can be seen from this figure, in the 4000 ppm-containing feed administration group, the tumor volume was significantly lower than the control group from 1 week to 6 weeks from the start of the experiment. In the feed administration group containing 2000 ppm, the tumor volume showed a significantly low value from 2 weeks to 6 weeks except at 5 weeks from the start of the experiment. At the end of the experiment, compared to the control group, the tumor volume was 26% in the feed administration group containing 2000 ppm and 38% in the feed administration group containing 4000 ppm, and the tumor volume was small.
- lymph node metastasis and lung metastasis The number of lymph node metastases per mouse (the number of metastasized lymph nodes) was significantly decreased in both the 2000 ppm-containing diet group and the 4000 ppm-containing diet group compared to the control group. The decrease was also statistically significant (FIG. 5a).
- lung metastases when the number of metastases was 1 mm or more and the number per mouse was calculated, both the 2000 ppm-containing feed group and the 4000 ppm-containing feed group showed a very marked decrease compared to the control group. was also statistically significant (FIG. 5b).
- the numerical value represents the average value in each group, and the error bar represents the standard deviation (hereinafter the same in the same kind of figures).
- the total number of metastasized organs is counted as above for lymph nodes and lungs, and for other organs, the left and right ovaries, adrenal glands, and kidneys are “1” if they are metastasizing only on one side, and both sides are metastasized. “2” if it was, and “1” if the liver and bone had metastasis.
- Dodecanoic acid (C 12 ) (5 g, 0.25 mol, Wako Pure Chemical Industries) was refluxed with thionyl chloride (7 ml, Wako Pure Chemical Industries) on a water bath for 2 hours, after which excess thionyl chloride was removed under reduced pressure. Distilled off to prepare dodecanoic acid chloride. ⁇ -Mangosteen (4.1 g, 0.01 mol) was dissolved in pyridine (3 ml) and tetrohydrofuran (30 ml), and this solution was added dropwise into dodecanoic acid chloride.
- reaction solution was heated on a water bath (3 hours), cooled, added to 1N hydrochloric acid (50 ml), and extracted with ethyl acetate.
- Example 2 The same treatment as in Example 1 was carried out except that 10-undecenoic acid (C 11 ) was used instead of dodecanoic acid to obtain ⁇ -mangostin 10-undecenoic acid diester as a pale yellow brown oily substance. (Physical constant of this product) Molecular formula: C 46 H 62 O 8 Molecular weight: 742 EIMS m / z (%): 742 (M + , 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72) , 325 (15).
- Example 5 Synthesis of ⁇ -mangosteen tetradecanoic acid diester
- the compound (1) of the present invention has an excellent anticancer activity and cancer metastasis inhibiting activity, it can be used in the fields of medicine and cancer treatment.
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Abstract
Provided is a novel compound having excellent anticancer activity and metastasis inhibition activity. An α-mangosteen diester represented by general formula (1): (in the formula, R1 represents the residue after a hydroxyl group is removed from a C8-14 medium chain triglyceride), and an anticancer agent or metastasis inhibiting agent including said compound as the active component thereof.
Description
本発明はキサントン誘導体およびその用途に関し、更に詳しくは優れた医薬作用を有するα-マンゴスチンC8-14中鎖脂肪酸ジエステルおよびその用途に関する。
The present invention relates to xanthone derivatives and uses thereof, and more particularly to α-mangostin C 8-14 medium chain fatty acid diesters having excellent pharmaceutical action and uses thereof.
マンゴスチン(mangosteen、学名:Garcinia mangostana L)は東南アジア原産のオトギリソウ科(Guttiferae)の常緑小高木である。その果実は世界三大果実の一つで、果実の女王と呼ばれており、東南アジアを代表する高級トロピカルフルーツである。果実の大きさは約5cm大の球形で、厚い果皮を持つ。果肉は白色でミカンの袋のように分かれており、これを食する。その果皮は黄色色素(キサントン類)を含み、古くから止血、鎮痛、防腐、消炎といった収斂剤として用いられてきており、民間伝承薬物として重要な天然資源である。
Mangosteen (scientific name: Garcinia mangostana L) is an evergreen small Takagi of Guttiferae native to Southeast Asia. The fruit is one of the three largest fruits in the world, called the fruit queen, and is a high-class tropical fruit that represents Southeast Asia. The size of the fruit is about 5cm in size and has a thick skin. The pulp is white and is divided like a mandarin orange bag. The pericarp contains yellow pigments (xanthones) and has long been used as an astringent such as hemostatic, analgesic, antiseptic and anti-inflammatory, and is an important natural resource as a folklore drug.
マンゴスチン果皮に含まれるキサントン誘導体の主成分はα-マンゴスチン(α-mangostin)およびγ-マンゴスチン(γ-mangostin)である。
The main components of xanthone derivatives contained in mangosteen peel are α-mangostin and γ-mangostin.
最近になって、α-およびγ-マンゴスチンは、抗菌作用、抗炎症作用、抗アレルギー作用及び抗癌作用を有することが報告された。具体的には、抗MRSA(メシチリン耐性黄色ブドウ球菌)活性(非特許文献1)、ヒスタミンおよびセロトニン受容体阻害活性(非特許文献2)、抗酸化活性(非特許文献3)、抗アレルギー活性(非特許文献4)、癌細胞に対するアポトーシス誘導能(非特許文献5)、細胞周期停止(非特許文献6)といった様々な生理活性であり、マンゴスチンの有する多彩な効果がそれらによって説明される。また、α-マンゴスチン又はγ-マンゴスチンを投与されたマウスおよびヒトでNK活性が上昇することも確認されている(非特許文献7、8)。さらに、マンゴスチンの抽出物であるパナキサントン(α-マンゴスチン75~85%およびγ-マンゴスチン5~15%の混合物で、両者の含量総和が90%以上のもの)がマウス乳癌に対して抗腫瘍効果を有すること(非特許文献9)や、α-マンゴスチンを20mg/kgの用量で浸透圧ポンプを用いてマウス乳癌に対して投与すると、生存率の延長やリンパ節転移の抑制が観察されたこと(非特許文献10、11)が報告されている。
Recently, α- and γ-mangosteen has been reported to have antibacterial, anti-inflammatory, antiallergic and anticancer effects. Specifically, anti-MRSA (mesitillin-resistant Staphylococcus aureus) activity (Non-patent document 1), histamine and serotonin receptor inhibitory activity (Non-patent document 2), antioxidant activity (Non-patent document 3), antiallergic activity ( Non-patent document 4), various physiological activities such as apoptosis-inducing ability against cancer cells (non-patent document 5), cell cycle arrest (non-patent document 6), and various effects of mangosteen are explained by them. It has also been confirmed that NK activity is increased in mice and humans administered with α-mangostin or γ-mangostin (Non-patent Documents 7 and 8). Furthermore, panaxanthone (a mixture of α-mangostin 75 to 85% and γ-mangostin 5 to 15%, and the total content of both is 90% or more) is an antitumor effect on mouse breast cancer. (Non-patent document 9), and when α-mangostin was administered to mouse breast cancer using an osmotic pump at a dose of 20 mg / kg, prolonged survival and suppression of lymph node metastasis were observed. (Non-Patent Documents 10 and 11) have been reported.
癌の終末像は転移による死である。乳癌においても死因のほとんどはリンパ節、肺などへの転移によるものであり、転移を抑制することは癌治療の最大の課題と言える。
The terminal image of cancer is death due to metastasis. Even in breast cancer, most of the causes of death are due to metastasis to lymph nodes, lungs, etc., and suppressing metastasis is the biggest problem in cancer treatment.
一方、α-マンゴスチンの誘導体としては、例えば、α-マンゴスチントリアセテートが知られており、この化合物は皮膚の審美的外観を改善する作用や毛細血管拡張症に対する治療作用を有するとされている(特許文献1)。
On the other hand, as a derivative of α-mangostin, for example, α-mangosteen triacetate is known, and this compound is said to have an action of improving the aesthetic appearance of the skin and a therapeutic action against telangiectasia (patent). Reference 1).
α-マンゴスチンは前述のように抗癌作用や癌転移抑制作用を有しているが、その作用は必ずしも十分でない。本発明の目的は、より優れた抗癌作用や癌転移抑制作用を有するα-マンゴスチン誘導体を提供することである。
Α-Mangosteen has an anticancer effect and a cancer metastasis inhibitory effect as described above, but its effect is not always sufficient. An object of the present invention is to provide an α-mangostin derivative having a more excellent anticancer activity and cancer metastasis suppressing activity.
本発明者らは、前記課題を解決すべく鋭意研究を重ねた結果、α-マンゴスチンのC8-14中鎖脂肪酸ジエステルがα-マンゴスチンに比べ顕著に優れた抗癌作用や癌転移抑制作用を有することを見出し、本発明を完成するに至った。
As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that C8-14 medium chain fatty acid diester of α-mangostin has significantly superior anticancer activity and cancer metastasis inhibitory activity compared to α-mangostin. As a result, the present invention has been completed.
すなわち、本発明は、
(1)一般式(1): That is, the present invention
(1) General formula (1):
(1)一般式(1): That is, the present invention
(1) General formula (1):
(式中、R1は炭素数8~14の中鎖脂肪酸から水酸基を除いた残基を表す。)
で示されるα-マンゴスチンジエステル、
(2)R1が炭素数8~14の飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(3)R1が炭素数8~14の不飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(4)R1がオクタン酸、ノナン酸、デカン酸、ウンデカン酸、ドデカン酸、トリデカン酸、テトラデカン酸から選ばれる飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(5)R1が10-ウンデセン酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル、
(6)式(1-a) (In the formula, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Α-mangosteen diester represented by
(2) The α-mangosteen diester as described in 1 above, wherein R 1 is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid having 8 to 14 carbon atoms,
(3) The α-mangosteen diester as described in 1 above, wherein R 1 is a residue obtained by removing a hydroxyl group from an unsaturated medium chain fatty acid having 8 to 14 carbon atoms,
(4) α-Mangosteen according to theabove item 1, wherein R 1 is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid selected from octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid and tetradecanoic acid. Diester,
(5) The α-mangosteen diester according toclaim 1, wherein R 1 is a residue obtained by removing a hydroxyl group from 10-undecenoic acid,
(6) Formula (1-a)
で示されるα-マンゴスチンジエステル、
(2)R1が炭素数8~14の飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(3)R1が炭素数8~14の不飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(4)R1がオクタン酸、ノナン酸、デカン酸、ウンデカン酸、ドデカン酸、トリデカン酸、テトラデカン酸から選ばれる飽和中鎖脂肪酸から水酸基を除いた残基である前記1項記載のα-マンゴスチンジエステル、
(5)R1が10-ウンデセン酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル、
(6)式(1-a) (In the formula, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Α-mangosteen diester represented by
(2) The α-mangosteen diester as described in 1 above, wherein R 1 is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid having 8 to 14 carbon atoms,
(3) The α-mangosteen diester as described in 1 above, wherein R 1 is a residue obtained by removing a hydroxyl group from an unsaturated medium chain fatty acid having 8 to 14 carbon atoms,
(4) α-Mangosteen according to the
(5) The α-mangosteen diester according to
(6) Formula (1-a)
で示されるα-マンゴスチンドデカン酸ジエステル、
(7)前記1~6項のいずれかのα-マンゴスチンジエステルを有効成分として含有する抗癌剤、および
(8)前記1~6項のいずれかのα-マンゴスチンジエステルを有効成分として含有する癌転移抑制剤、
である。 Α-mangosteen dodecanoic acid diester represented by
(7) An anticancer agent containing the α-mangosteen diester according to any one ofitems 1 to 6 as an active ingredient, and (8) Suppression of cancer metastasis containing the α-mangostin diester according to any one of items 1 to 6 as an active ingredient Agent,
It is.
(7)前記1~6項のいずれかのα-マンゴスチンジエステルを有効成分として含有する抗癌剤、および
(8)前記1~6項のいずれかのα-マンゴスチンジエステルを有効成分として含有する癌転移抑制剤、
である。 Α-mangosteen dodecanoic acid diester represented by
(7) An anticancer agent containing the α-mangosteen diester according to any one of
It is.
本発明にかかるα-マンゴスチンジエステル(1)は、優れた抗癌作用や癌転移抑制作用を有することから、抗癌剤や癌転移抑制剤として有用である。
The α-mangostin diester (1) according to the present invention is useful as an anticancer agent or cancer metastasis inhibitor since it has an excellent anticancer activity and cancer metastasis inhibitory activity.
本発明の化合物は、一般式(1):
The compound of the present invention has the general formula (1):
(式中、R1は炭素数8~14の中鎖脂肪酸から水酸基を除いた残基を表す。)
で示されるα-マンゴスチンジエステルである。 (In the formula, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
An α-mangosteen diester represented by the formula:
で示されるα-マンゴスチンジエステルである。 (In the formula, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
An α-mangosteen diester represented by the formula:
R1は炭素数8~14の中鎖脂肪酸から水酸基を除いた残基であるが、ここで「炭素数8~14の中鎖脂肪酸」とは、オクタン酸(C8)(=カプリル酸)、ノナン酸(C9)(=ペラルゴン酸)、デカン酸(C10)(=カプリン酸)、ウンデカン酸(C11)、ドデカン酸(C12)(=ラウリン酸)、トリデカン酸(C13)、テトラデカン酸(C14)(=ミリスチン酸)などの炭素数8~14の飽和中鎖脂肪酸、ならびに10-ウンデセン酸(C11)などの炭素数8~14の不飽和中鎖脂肪酸を含む。これらのうち、炭素数8~12の飽和または不飽和中鎖脂肪酸がより好ましく、とりわけ炭素数10~12の飽和中鎖脂肪酸が好ましい。
本発明のα-マンゴスチンジエステル(1)において、かかる二つのエステル結合は、C8-14中鎖脂肪酸がキサントン骨格の3位及び6位の水酸基と結合して、形成されたものである。 R 1 is a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms. Here, “medium chain fatty acid having 8 to 14 carbon atoms” means octanoic acid (C 8 ) (= caprylic acid). Nonanoic acid (C 9 ) (= pelargonic acid), decanoic acid (C 10 ) (= capric acid), undecanoic acid (C 11 ), dodecanoic acid (C 12 ) (= lauric acid), tridecanoic acid (C 13 ) , Saturated medium chain fatty acids having 8 to 14 carbon atoms such as tetradecanoic acid (C 14 ) (= myristic acid), and unsaturated medium chain fatty acids having 8 to 14 carbon atoms such as 10-undecenoic acid (C 11 ). Of these, saturated or unsaturated medium chain fatty acids having 8 to 12 carbon atoms are more preferable, and saturated medium chain fatty acids having 10 to 12 carbon atoms are particularly preferable.
In the α-mangosteen diester (1) of the present invention, these two ester bonds are formed by combining C 8-14 medium chain fatty acids with hydroxyl groups at the 3rd and 6th positions of the xanthone skeleton.
本発明のα-マンゴスチンジエステル(1)において、かかる二つのエステル結合は、C8-14中鎖脂肪酸がキサントン骨格の3位及び6位の水酸基と結合して、形成されたものである。 R 1 is a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms. Here, “medium chain fatty acid having 8 to 14 carbon atoms” means octanoic acid (C 8 ) (= caprylic acid). Nonanoic acid (C 9 ) (= pelargonic acid), decanoic acid (C 10 ) (= capric acid), undecanoic acid (C 11 ), dodecanoic acid (C 12 ) (= lauric acid), tridecanoic acid (C 13 ) , Saturated medium chain fatty acids having 8 to 14 carbon atoms such as tetradecanoic acid (C 14 ) (= myristic acid), and unsaturated medium chain fatty acids having 8 to 14 carbon atoms such as 10-undecenoic acid (C 11 ). Of these, saturated or unsaturated medium chain fatty acids having 8 to 12 carbon atoms are more preferable, and saturated medium chain fatty acids having 10 to 12 carbon atoms are particularly preferable.
In the α-mangosteen diester (1) of the present invention, these two ester bonds are formed by combining C 8-14 medium chain fatty acids with hydroxyl groups at the 3rd and 6th positions of the xanthone skeleton.
本発明のα-マンゴスチンジエステル(1)の具体例としては、例えばα-マンゴスチンオクタン酸ジエステル(=α-マンゴスチンカプリル酸ジエステル)、α-マンゴスチンノナン酸ジエステル(=α-マンゴスチンペラルゴン酸ジエステル)、α-マンゴスチンデカン酸ジエステル(=α-マンゴスチンカプリン酸ジエステル)、α-マンゴスチンドデカン酸ジエステル(=α-マンゴスチンラウリン酸ジエステル)、α-マンゴスチンテトラデカン酸ジエステル(=α-マンゴスチンミリスチン酸ジエステル)、α-マンゴスチン10-ウンデセン酸ジエステルが挙げられる。これらのうちでは、α-マンゴスチンオクタン酸ジエステル、α-マンゴスチンデカン酸ジエステル、α-マンゴスチンドデカン酸ジエステルおよびα-マンゴスチン10-ウンデセン酸ジエステルが好ましく、とりわけα-マンゴスチンドデカン酸ジエステルが好ましい。ちなみにα-マンゴスチンドデカン酸ジエステルは、1,3,6-トリヒドロキシ-7-メトキシ-2,8-ジ(3-メチル-2-ブテニル)キサントン・3,6-O-ジドデカノエートの化学名でも表され、構造式で示せば、次の通りである。
Specific examples of the α-mangosteen diester (1) of the present invention include, for example, α-mangosteen octanoic acid diester (= α-mangosteen caprylic acid diester), α-mangosteen nonanoic acid diester (= α-mangosteen pelargonic acid diester), α Mangosteen decanoic acid diester (= α-mangosteen capric acid diester), α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester), α-mangosteen tetradecanoic acid diester (= α-mangosteen myristic acid diester), α-mangosteen And 10-undecenoic acid diester. Of these, α-mangosteen octanoic acid diester, α-mangosteen decanoic acid diester, α-mangosteen dodecanoic acid diester and α-mangostin 10-undecenoic acid diester are preferable, and α-mangosteen dodecanoic acid diester is particularly preferable. Incidentally, α-mangosteen dodecanoic acid diester is also represented by the chemical name of 1,3,6-trihydroxy-7-methoxy-2,8-di (3-methyl-2-butenyl) xanthone and 3,6-O-didodecanoate. The structural formula is as follows.
本発明のα-マンゴスチンジエステル(1)は、次式:
The α-mangosteen diester (1) of the present invention has the following formula:
で示されるα-マンゴスチンと、一般式(2):
Α-mangosteen represented by the general formula (2):
(ただし、R1は炭素数8~14の中鎖脂肪酸から水酸基を除いた残基を表す。)
で示されるC8-14中鎖脂肪酸またはそのカルボキシル基における反応性誘導体とを、エステル化反応に付すことにより製造することができる。 (However, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Can be produced by subjecting the C 8-14 medium chain fatty acid represented by the above formula or a reactive derivative in the carboxyl group thereof to an esterification reaction.
で示されるC8-14中鎖脂肪酸またはそのカルボキシル基における反応性誘導体とを、エステル化反応に付すことにより製造することができる。 (However, R 1 represents a residue obtained by removing a hydroxyl group from a medium chain fatty acid having 8 to 14 carbon atoms.)
Can be produced by subjecting the C 8-14 medium chain fatty acid represented by the above formula or a reactive derivative in the carboxyl group thereof to an esterification reaction.
一般式(2)で示される化合物のカルボキシル基における反応性誘導体としては、常法に従って得られる、例えば酸ハロゲン化物、酸無水物、活性化アミド、活性化エステルなどが挙げられる。そのような反応性誘導体の好適な例としては、酸塩化物;酸アジ化物;例えばジアルキルリン酸、フェニルリン酸、ジフェニルリン酸、ジベンジルリン酸、ハロゲン化リン酸などの置換されたリン酸、ジアルキル亜リン酸、亜硫酸、チオ硫酸、硫酸、例えばメタンスルホン酸などのスルホン酸、例えば酢酸、プロピオン酸、酪酸、イソ酪酸、ピバリン酸、ペンタン酸、イソペンタン酸、トリクロロ酢酸などの脂肪族カルボン酸、または例えば安息香酸などの芳香族カルボン酸のような酸との混合酸無水物;対称酸無水物;イミダゾール、4-置換イミダゾール、ジメチルピラゾール、トリアゾールまたはテトラゾールとの活性アミド、または例えばシアノメチルエステル、メトキシメチルエステル、ジメチルイミノメチルエステル、ビニルエステル、プロパルギルエステル、p-ニトロフェニルエステル、トリクロロフェニルエステル、ペンタクロロフェニルエステル、メシルフェニルエステル、フェニルアゾフェニルエステル、フェニルチオエステル、p-ニトロフェニルエステル、p-クレジルチオエステル、カルボキシメチルチオエステル、ピラニルエステル、ピリジルエステル、ピペリジルエステル、8-キノリルチオエステル等などの活性化エステル、または例えばN,N-ジメチルヒドロキシアミン、N-ヒドロキシ-2-(1H)-ピリドン、N-ヒドロキシスクシンイミド、N-ヒドロキシフタルイミド、1-ヒドロキシ-1H-ベンゾトリアゾール、N-ヒドロキシ-5-ノルボルネン-2,3-ジカルボキシイミドなどのN-ヒドロキシ化合物のエステルなどが挙げられる。これら反応性誘導体は、使用する一般式(2)の化合物の種類によって任意に選択することができる。
Examples of the reactive derivative at the carboxyl group of the compound represented by the general formula (2) include acid halides, acid anhydrides, activated amides, activated esters and the like obtained according to a conventional method. Suitable examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl Phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, for example acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid and other aliphatic carboxylic acids, or Mixed anhydrides with acids such as aromatic carboxylic acids such as benzoic acid; symmetrical anhydrides; active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, or eg cyanomethyl esters, methoxy Methyl ester, dimethyliminomethyl ester, vinyl ester Ter, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl ester, p-cresylthioester, carboxymethylthioester, pyranyl ester, Activated esters such as pyridyl esters, piperidyl esters, 8-quinolyl thioesters, etc., or, for example, N, N-dimethylhydroxyamine, N-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, And esters of N-hydroxy compounds such as 1-hydroxy-1H-benzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide . These reactive derivatives can be arbitrarily selected depending on the type of the compound of the general formula (2) to be used.
エステル化反応は、通常、水、例えばメタノール、エタノールなどのアルコール類、アセトン、ジオキサン、アセトニトリル、クロロホルム、塩化メチレン、塩化エチレン、テトラヒドロフラン、酢酸エチル、N,N-ジメチルホルムアミド、ピリジンのような常用の溶媒中で行われるが、反応に悪影響を及ぼさない溶媒であればその他のいかなる有機溶媒中でも反応を行うことができる。これら常用の溶媒は水との混合物として使用してもよい。
The esterification reaction is usually water, for example, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, and pyridine. The reaction can be performed in any other organic solvent as long as it is performed in a solvent but does not adversely affect the reaction. These common solvents may be used as a mixture with water.
一般式(2)の化合物を遊離酸の形またはその塩の形で使用する場合には、例えばN,N’-ジシクロヘキシルカルボジイミド;N-シクロヘキシル-N’-モルホリノエチルカルボジイミド;N-シクロヘキシル-N’-(4-ジエチルアミノシクロヘキシル)カルボジイミド;N,N’-ジエチルカルボジイミド、N,N’-ジイソプロピルカルボジイミド、N-エチル-N’-(3-ジメチルアミノプロピル)カルボジイミド;N,N’-カルボニルビス(2-メチルイミダゾ-ル);ペンタメチレンケテン-N-シクロヘキシルイミン;ジフェニルケテン-N-シクロヘキシルイミン;エトキシアセチレン;1-アルコキシ-1-クロロエチレン;亜リン酸トリアルキル;ポリリン酸エチル;ポリリン酸イソプロピル;オキシ塩化リン;ジフェニルホスホリルアジド;塩化チオニル;塩化オキサリル;例えばクロロギ酸エチル、クロロギ酸イソプロピル等のハロギ酸低級アルキル;トリフェニルホスフィン;2-エチル-7-ヒドロキシベンズイソオキサゾリウム塩、2-エチル-5-(m-スルホフェニル)イソオキサゾリウムヒドロキシド分子内塩;N-ヒドロキシベンゾトリアゾ-ル;1-(p-クロロベンゼンスルホニルオキシ)-6-クロロ-1H-ベンゾトリアゾ-ル;N,N’-ジメチルホルムアミドと塩化チオニル、ホスゲン、クロロギ酸トリクロロメチルまたはオキシ塩化リン等との反応によって調製したいわゆるビルスマイヤ-試薬等のような常用の縮合剤の存在下に反応を行うのが望ましい。また、N-ヒドロシキベンゾトリアゾールまたはN-ヒドロキシ-5-ノルボルネン-エンド-2,3-ジカルボキシイミドの存在下、N,N’-ジシクロヘキシルカルボジイミド等の縮合剤を用いる方法も望ましい。
When the compound of the general formula (2) is used in the form of a free acid or a salt thereof, for example, N, N′-dicyclohexylcarbodiimide; N-cyclohexyl-N′-morpholinoethylcarbodiimide; N-cyclohexyl-N ′ -(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2 -Methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; Oxychloride Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5 -(M-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N ' It is desirable to carry out the reaction in the presence of a conventional condensing agent such as a so-called Vilsmeier reagent prepared by reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate or phosphorus oxychloride. A method using a condensing agent such as N, N′-dicyclohexylcarbodiimide in the presence of N-hydroxybenzotriazole or N-hydroxy-5-norbornene-endo-2,3-dicarboximide is also desirable.
反応はまたアルカリ金属炭酸水素塩トリ(低級)アルキルアミン、ピリジン、N-(低級)-アルキルモルホリン、N,N-ジ(低級)アルキルベンジルアミン等のような無機塩基または有機塩基の存在下に行ってもよい。原料であるα-マンゴスチンと一般式(2)の化合物またはそのカルボキシル基における反応性誘導体との使用割合は、前者1モルに対し、通常後者2モル以上であり、好ましくは5~50モルである。反応温度は特に限定されないが、通常は冷却下ないし加温下(-10~120℃)に反応が行われる。反応時間は通常約0.5時間~約10時間、好ましくは約1時間~約5時間である。
The reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonates tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. You may go. The use ratio of α-mangostin as a raw material to the compound of the general formula (2) or a reactive derivative thereof in the carboxyl group is usually 2 mol or more, preferably 5 to 50 mol, with respect to 1 mol of the former. . The reaction temperature is not critical, but the reaction is usually carried out under cooling to warming (-10 to 120 ° C.). The reaction time is usually about 0.5 hour to about 10 hours, preferably about 1 hour to about 5 hours.
このようにして得られるα-マンゴスチンジエステル(1)は、公知の分離精製手段、例えば濃縮、減圧濃縮、溶媒留出、晶出、転溶、クロマトグラフィーなどにより単離精製することができる。
The α-mangosteen diester (1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent distillation, crystallization, transfer dissolution, chromatography and the like.
原料化合物(2)は、例えばPhytochemistry 1995, 39, 943-944に記載されている方法により製造することができる。
Raw material compound (2) can be produced, for example, by the method described in Phytochemistry 1995, 39, 943-944.
かくして得られたα-マンゴスチンジエステル(1)(以下、適宜、化合物(1)と称する。)は、優れた抗癌作用や癌転移抑制作用を有することから、抗癌剤または癌転移抑制剤として使用することができる。対象となる癌は特に制限されず、種々の癌(例えば、乳癌、前立腺癌、膵癌、胃癌、肺癌、結腸癌、直腸癌、食道癌、十二指腸癌、舌癌、咽頭癌、脳腫瘍、神経鞘腫、非小細胞肺癌、肺小細胞癌、肝臓癌、腎臓癌、胆管癌、子宮体癌、子宮頚癌、卵巣癌、膀胱癌、皮膚癌、血管系腫瘍、悪性リンパ腫、悪性黒色腫、甲状腺癌、骨腫瘍、副腎腫瘍、網膜腫瘍)に適用できる。
本発明の化合物(1)を抗癌剤または癌転移抑制剤として使用する場合、ヒトのみならず、ヒト以外の哺乳動物(例えば、ウマ、ウシ、イヌ、ネコ、ブタ、サルなど)に対しても使用することができる。 The α-mangosteen diester (1) thus obtained (hereinafter appropriately referred to as compound (1)) has excellent anticancer activity and cancer metastasis inhibitory activity, and is therefore used as an anticancer agent or cancer metastasis inhibitor. be able to. The target cancer is not particularly limited, and various cancers (for example, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma) Non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, vascular tumor, malignant lymphoma, malignant melanoma, thyroid cancer , Bone tumor, adrenal tumor, retinal tumor).
When the compound (1) of the present invention is used as an anticancer agent or a cancer metastasis inhibitor, it is used not only for humans but also for mammals other than humans (for example, horses, cows, dogs, cats, pigs, monkeys, etc.). can do.
本発明の化合物(1)を抗癌剤または癌転移抑制剤として使用する場合、ヒトのみならず、ヒト以外の哺乳動物(例えば、ウマ、ウシ、イヌ、ネコ、ブタ、サルなど)に対しても使用することができる。 The α-mangosteen diester (1) thus obtained (hereinafter appropriately referred to as compound (1)) has excellent anticancer activity and cancer metastasis inhibitory activity, and is therefore used as an anticancer agent or cancer metastasis inhibitor. be able to. The target cancer is not particularly limited, and various cancers (for example, breast cancer, prostate cancer, pancreatic cancer, stomach cancer, lung cancer, colon cancer, rectal cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain tumor, schwannoma) Non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, vascular tumor, malignant lymphoma, malignant melanoma, thyroid cancer , Bone tumor, adrenal tumor, retinal tumor).
When the compound (1) of the present invention is used as an anticancer agent or a cancer metastasis inhibitor, it is used not only for humans but also for mammals other than humans (for example, horses, cows, dogs, cats, pigs, monkeys, etc.). can do.
本発明の化合物(1)を抗癌剤または癌転移抑制剤として使用する場合には、それ自体あるいは適宜の薬理学的に許容される、賦形剤、希釈剤などと混合し、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤などに製剤化して経口的に投与するか、又は静脈内注射剤、筋肉内注射剤などに製剤化して非経口的に投与することができる。
When the compound (1) of the present invention is used as an anticancer agent or cancer metastasis inhibitor, it is mixed with itself or appropriate pharmacologically acceptable excipients, diluents, etc., and tablets, capsules, It can be formulated into granules, powders, syrups, etc. and administered orally, or can be formulated into intravenous injections, intramuscular injections, etc. and administered parenterally.
これらの製剤は、賦形剤(例えば、乳糖、白糖、ブドウ糖、マンニット、ソルビットのような糖誘導体;トウモロコシデンプン、馬鈴薯デンプン、α-デンプン、デキストリン、カルボキシメチルデンプンのようなデンプン誘導体;結晶セルロ-ス、低置換度ヒドロキシプロピルセルロ-ス、ヒドロキシプロピルメチルセルロ-ス、カルボキシメチルセルロ-ス、カルボキシメチルセルロ-スカルシウム、内部架橋カルボキシメチルセルロ-スナトリウムのようなセルロ-ル誘導体;アラビアゴム;デキストラン;プルラン;軽質無水珪酸、合成珪酸アルミニウム、メタ珪酸アルミン酸マグネシウムのような珪酸塩誘導体;リン酸カルシウムのようなリン酸塩誘導体;炭酸カルシウムのような炭酸塩誘導体;硫酸カルシウムのような硫酸塩誘導体等)、結合剤(例えば、前記の賦形剤;ゼラチン;ポリビニルピロリドン;マグロゴ-ル等)、崩壊剤(例えば、前記の賦形剤;クロスカルメロ-スナトリウム、カルボキシメチルスタ-チナトリウム、架橋ポリビニルピロリドンのような化学修飾された、デンプン、セルロ-ス誘導体等)、滑沢剤(例えば、タルク;ステアリン酸;ステアリン酸カルシウム、ステアリン酸マグネシウムのようなステアリン酸金属塩;コロイドシリカ;ビ-ガム,ゲイロウのようなラックス類;硼酸;グリコ-ル;フマル酸、アジピン酸のようなカルボン酸類;安息香酸ナトリウムのようなカルボン酸ナトリウム塩;硫酸ナトリウムのような硫酸類塩;ロイシン;ラウリル硫酸ナトリウム、ラウリル硫酸マグネシウムのようなラウリル硫酸塩;無水珪酸、珪酸水和物のような珪酸類;前記の賦形剤におけるデンプン誘導体等)、安定剤(例えば、メチルパラベン、プロピルバラベンのようなパラオキシ安息香酸エステル類;クロロブタノ-ル、ベンジルアルコ-ル、フェニルエチルアルコ-ルのようなアルコ-ル類;塩化ベンザルコニウム;フェノ-ル、クレゾ-ルのようなフェノ-ル類;チメロサ-ル;無水酢酸;ソルビン酸等)、矯味矯臭剤(例えば、通常使用される、甘味料、酸味料、香料等)、懸濁化剤(例えば、ポリソルベ-ト80、カルボキシメチルセルロ-スナトリウム等)、希釈剤、製剤用溶剤(例えば、水、エタノ-ル、グリセリン等)等の添加物を用いて周知の方法で製造される。
These preparations are made of excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose -Cellulose derivatives such as low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic Dextran; pullulan; silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfates such as calcium sulfate Conductors, etc.), binders (for example, the aforementioned excipients; gelatin; polyvinylpyrrolidone; maglogol, etc.), disintegrants (for example, the aforementioned excipients; croscarmellose sodium, sodium carboxymethyl starch, Chemically modified starch such as cross-linked polyvinyl pyrrolidone, cellulose derivatives, etc.), lubricant (eg talc; stearic acid; stearic acid; metal stearate such as calcium stearate, magnesium stearate; colloidal silica; beer Luxes such as gums and gallows; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylates such as sodium benzoate; sulfates such as sodium sulfate; leucine; lauryl sulfate Sodium, lauryl sulfate such as magnesium lauryl sulfate; silicic anhydride Silicic acids such as silicic acid hydrate; starch derivatives in the above-mentioned excipients, etc., stabilizers (for example, para-oxybenzoic acid esters such as methylparaben and propylbaraben; chlorobutanol, benzyl alcohol, phenyl) Alcohols such as ethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.], flavoring agents (for example, Commonly used sweeteners, acidulants, fragrances, etc.), suspending agents (eg, polysorbate 80, carboxymethyl cellulose sodium, etc.), diluents, formulation solvents (eg, water, ethanol) , Glycerin and the like) and other additives.
本発明の化合物(1)の投与量は、年齢、体重、症状等、並びに、投与形態、および、投与回数によって異なるが、通常、成人(体重50kg)に対して、1日1~2000mg、特に10~500mg程度を1回、または、数回に分けて投与するのが好ましい。
The dose of the compound (1) of the present invention varies depending on the age, body weight, symptoms, etc., and the administration form and the number of administrations, but is usually 1 to 2000 mg per day for an adult (body weight 50 kg), particularly About 10 to 500 mg is preferably administered once or divided into several times.
本発明の化合物(1)は、他の抗癌剤または癌転移抑制剤と併用することができる。該併用剤としては、例えば、アドリアマイシン、マイトマイシン、5-フルオロウラシル、イリノテカン、タキソールなどが挙げられる。併用の場合において、それぞれの薬剤の投与時期は限定されず、同時にあるいは時間差をおいて投与してもよい。本発明の化合物(1)と併用される薬剤との配合比は、投与対象、投与ルート、対象疾患、症状、組合せ等に応じて適宜選択することができる。
The compound (1) of the present invention can be used in combination with other anticancer agents or cancer metastasis inhibitors. Examples of the concomitant agent include adriamycin, mitomycin, 5-fluorouracil, irinotecan, taxol and the like. In the case of combined use, the administration timing of each drug is not limited, and may be administered simultaneously or with a time difference. The compounding ratio of the compound (1) of the present invention to the drug used in combination can be appropriately selected according to the administration subject, administration route, target disease, symptom, combination and the like.
以下に、試験例、比較例、実施例を示して、本発明をさらに詳しく説明するが、これらは、単なる例であって本発明を何ら制限するものではない。
Hereinafter, the present invention will be described in more detail with reference to test examples, comparative examples, and examples, but these are merely examples and do not limit the present invention in any way.
[試験例1]
(被験物質および飼料調製)
所定量のα-マンゴスチンドデカン酸ジエステル(=α-マンゴスチンラウリン酸ジエステル)を秤量し、コーンオイル(ナカライテスク株式会社)とともに50℃で加温・溶解し、粉末飼料CE-2(日本クレア株式会社)に混合した。 [Test Example 1]
(Test substance and feed preparation)
A predetermined amount of α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) is weighed and dissolved with corn oil (Nacalai Tesque) at 50 ° C., and then powdered feed CE-2 (Nippon Claire Co., Ltd.). ).
(被験物質および飼料調製)
所定量のα-マンゴスチンドデカン酸ジエステル(=α-マンゴスチンラウリン酸ジエステル)を秤量し、コーンオイル(ナカライテスク株式会社)とともに50℃で加温・溶解し、粉末飼料CE-2(日本クレア株式会社)に混合した。 [Test Example 1]
(Test substance and feed preparation)
A predetermined amount of α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) is weighed and dissolved with corn oil (Nacalai Tesque) at 50 ° C., and then powdered feed CE-2 (Nippon Claire Co., Ltd.). ).
(乳癌細胞株)
本実験で用いた乳癌細胞株BJMC3879Luc2は、BALB/c系マウスにMMTV(マウス乳癌ウィルス)を接種することにより誘発された乳癌より樹立されたBJMC3879細胞株にルシフェラーゼ遺伝子を安定的に組み込んだものである(Anticancer Res 29:4389-4396, 2009参照)。BJMC3879細胞株を同系マウスに移植するとリンパ節や肺に高率に転移を起こす(Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25:1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007参照)。 (Breast cancer cell line)
The breast cancer cell line BJMC3879Luc2 used in this experiment is one in which a luciferase gene is stably integrated into a BJMC3879 cell line established from breast cancer induced by inoculating BALB / c mice with MMTV (mouse breast cancer virus). Yes (see Anticancer Res 29: 4389-4396, 2009). Transplanting the BJMC3879 cell line into syngeneic mice causes a high rate of metastasis to lymph nodes and lungs (Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25: 1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007).
本実験で用いた乳癌細胞株BJMC3879Luc2は、BALB/c系マウスにMMTV(マウス乳癌ウィルス)を接種することにより誘発された乳癌より樹立されたBJMC3879細胞株にルシフェラーゼ遺伝子を安定的に組み込んだものである(Anticancer Res 29:4389-4396, 2009参照)。BJMC3879細胞株を同系マウスに移植するとリンパ節や肺に高率に転移を起こす(Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25:1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007参照)。 (Breast cancer cell line)
The breast cancer cell line BJMC3879Luc2 used in this experiment is one in which a luciferase gene is stably integrated into a BJMC3879 cell line established from breast cancer induced by inoculating BALB / c mice with MMTV (mouse breast cancer virus). Yes (see Anticancer Res 29: 4389-4396, 2009). Transplanting the BJMC3879 cell line into syngeneic mice causes a high rate of metastasis to lymph nodes and lungs (Cancer Gene Ther 9: 16-27, 2002; Carcinogenesis 25: 1887-1898, 2004; Cancer Gene ther 14: 268-278, 2007).
(インビボ乳癌モデル実験)
6週齡のBALB/c系雌マウス(日本SLC)の鼠径部皮下にBJMC3879Luc2細胞(2.5×106個/0.3ml)を移植し、腫瘍径が0.3~0.4cmになった時点で、α-マンゴスチンドデカン酸ジエステル含有飼料(0ppm[対照群]、2000ppmおよび4000ppm)を各群10匹(合計30匹)のマウスに6週間自由摂取させた。各群10匹のマウスは、5匹ずつに分けて二つのケージに収容した。毎週、摂餌量をケージ毎に測定し、また体重と乳腺腫瘍のサイズを個体別に測定した。乳腺腫瘍はデジタル式キャリパスで短径と長径を計測し、その体積を長径×(短径)2×0.4の算出式で求めた(EMBO J. 18: 2692-2701, 1999参照)。実験開始の7週時には、全生存動物を屠殺剖検し、乳腺腫瘍を摘出し、10%緩衝ホルマリン溶液にて固定した。肺およびリンパ節(腋窩部、鼡径部)を採取し、更に肉眼的異常が観察されたリンパ節や諸臓器・組織についても採取し、病理組織学的に検索した。 (In vivo breast cancer model experiment)
BJMC3879Luc2 cells (2.5 × 10 6 cells / 0.3 ml) were transplanted subcutaneously into the groin area of 6-week-old BALB / c female mice (Japan SLC), resulting in a tumor diameter of 0.3 to 0.4 cm. At that time, α-mangosteen dodecanoic acid diester-containing diet (0 ppm [control group], 2000 ppm and 4000 ppm) was freely given to 10 mice in each group (30 mice in total) for 6 weeks. Ten mice in each group were housed in two cages in groups of five. Weekly, food intake was measured for each cage, and body weight and mammary tumor size were measured for each individual. Breast tumors were measured for short diameter and long diameter with a digital caliper, and the volume was determined by the formula of long diameter x (short diameter) 2 x 0.4 (see EMBO J. 18: 2692-2701, 1999). At 7 weeks after the start of the experiment, all surviving animals were sacrificed and necropsied, and mammary tumors were removed and fixed with 10% buffered formalin solution. Lungs and lymph nodes (axillary region, inguinal region) were collected, and lymph nodes and various organs and tissues in which gross abnormalities were observed were also collected and histopathologically searched.
6週齡のBALB/c系雌マウス(日本SLC)の鼠径部皮下にBJMC3879Luc2細胞(2.5×106個/0.3ml)を移植し、腫瘍径が0.3~0.4cmになった時点で、α-マンゴスチンドデカン酸ジエステル含有飼料(0ppm[対照群]、2000ppmおよび4000ppm)を各群10匹(合計30匹)のマウスに6週間自由摂取させた。各群10匹のマウスは、5匹ずつに分けて二つのケージに収容した。毎週、摂餌量をケージ毎に測定し、また体重と乳腺腫瘍のサイズを個体別に測定した。乳腺腫瘍はデジタル式キャリパスで短径と長径を計測し、その体積を長径×(短径)2×0.4の算出式で求めた(EMBO J. 18: 2692-2701, 1999参照)。実験開始の7週時には、全生存動物を屠殺剖検し、乳腺腫瘍を摘出し、10%緩衝ホルマリン溶液にて固定した。肺およびリンパ節(腋窩部、鼡径部)を採取し、更に肉眼的異常が観察されたリンパ節や諸臓器・組織についても採取し、病理組織学的に検索した。 (In vivo breast cancer model experiment)
BJMC3879Luc2 cells (2.5 × 10 6 cells / 0.3 ml) were transplanted subcutaneously into the groin area of 6-week-old BALB / c female mice (Japan SLC), resulting in a tumor diameter of 0.3 to 0.4 cm. At that time, α-mangosteen dodecanoic acid diester-containing diet (0 ppm [control group], 2000 ppm and 4000 ppm) was freely given to 10 mice in each group (30 mice in total) for 6 weeks. Ten mice in each group were housed in two cages in groups of five. Weekly, food intake was measured for each cage, and body weight and mammary tumor size were measured for each individual. Breast tumors were measured for short diameter and long diameter with a digital caliper, and the volume was determined by the formula of long diameter x (short diameter) 2 x 0.4 (see EMBO J. 18: 2692-2701, 1999). At 7 weeks after the start of the experiment, all surviving animals were sacrificed and necropsied, and mammary tumors were removed and fixed with 10% buffered formalin solution. Lungs and lymph nodes (axillary region, inguinal region) were collected, and lymph nodes and various organs and tissues in which gross abnormalities were observed were also collected and histopathologically searched.
(癌転移の生体イメージング)
実験開始から6週間経過後、各群より無作為に1ケージを選び、そこに収容されている5匹のマウスについて、1匹当たり3mgのルシフェリンカリウム塩を腹腔内に投与し、イソフルレン吸入麻酔下にて、光子撮像装置(Photon Imager)(Biospace社)を用いて、生体発光イメージングを行い、転移の拡がりを群間で比較した。但し、対照群では、死亡例や瀕死例が観察されたため、これらに代えて残りのケージよりマウスを補充して、測定を行った。 (In vivo imaging of cancer metastasis)
Six weeks after the start of the experiment, one cage was randomly selected from each group, and 5 mice housed therein were administered intraperitoneally with 3 mg of luciferin potassium salt per mouse, under isoflurane inhalation anesthesia. Then, bioluminescence imaging was performed using a photon imaging device (Photon Imager) (Biospace), and the spread of metastasis was compared between groups. However, in the control group, since death cases and drowning cases were observed, instead of these, mice were supplemented from the remaining cages, and measurement was performed.
実験開始から6週間経過後、各群より無作為に1ケージを選び、そこに収容されている5匹のマウスについて、1匹当たり3mgのルシフェリンカリウム塩を腹腔内に投与し、イソフルレン吸入麻酔下にて、光子撮像装置(Photon Imager)(Biospace社)を用いて、生体発光イメージングを行い、転移の拡がりを群間で比較した。但し、対照群では、死亡例や瀕死例が観察されたため、これらに代えて残りのケージよりマウスを補充して、測定を行った。 (In vivo imaging of cancer metastasis)
Six weeks after the start of the experiment, one cage was randomly selected from each group, and 5 mice housed therein were administered intraperitoneally with 3 mg of luciferin potassium salt per mouse, under isoflurane inhalation anesthesia. Then, bioluminescence imaging was performed using a photon imaging device (Photon Imager) (Biospace), and the spread of metastasis was compared between groups. However, in the control group, since death cases and drowning cases were observed, instead of these, mice were supplemented from the remaining cages, and measurement was performed.
(統計学的解析)
対照群と投与群との間の生存率の統計解析にはホルム-シダック(Holm-Sidak)法による検定を、定量的データではスチューデントのt検定を行った。発生頻度の解析にはフィシャーの正確確率検定を用いた。 (Statistical analysis)
The statistical analysis of the survival rate between the control group and the treatment group was performed by the Holm-Sidak method, and the quantitative data was the Student's t-test. Fisher's exact test was used to analyze the frequency of occurrence.
対照群と投与群との間の生存率の統計解析にはホルム-シダック(Holm-Sidak)法による検定を、定量的データではスチューデントのt検定を行った。発生頻度の解析にはフィシャーの正確確率検定を用いた。 (Statistical analysis)
The statistical analysis of the survival rate between the control group and the treatment group was performed by the Holm-Sidak method, and the quantitative data was the Student's t-test. Fisher's exact test was used to analyze the frequency of occurrence.
(結果)
1.生存率
生存率は図1の通りである。この図から明らかなように、対照群では6週時及び7週時に合わせて5例の死亡例(5/10)を観察したのに対し、検体2000ppm含有飼料投与群で7週時に1例の死亡例(1/10)を観察したのみであり、4000ppm含有飼料投与群では死亡例を全く認めなかった(0/10)。すなわち、実験終了時の生存率は対照群で50%、2000ppm含有飼料投与群で90%、4000ppm含有飼料投与群で100%であり、対照群と4000ppm含有飼料投与群の間に統計学的な差が観察された。 (result)
1. Survival rate The survival rate is as shown in FIG. As is apparent from this figure, 5 death cases (5/10) were observed at the 6th and 7th week in the control group, whereas one case at 7th week in the feed administration group containing thespecimen 2000 ppm. Only death cases (1/10) were observed, and no death cases were observed in the 4000 ppm feed administration group (0/10). That is, the survival rate at the end of the experiment is 50% in the control group, 90% in the feed administration group containing 2000 ppm, 100% in the feed administration group containing 4000 ppm, and statistically between the control group and the feed administration group containing 4000 ppm. Differences were observed.
1.生存率
生存率は図1の通りである。この図から明らかなように、対照群では6週時及び7週時に合わせて5例の死亡例(5/10)を観察したのに対し、検体2000ppm含有飼料投与群で7週時に1例の死亡例(1/10)を観察したのみであり、4000ppm含有飼料投与群では死亡例を全く認めなかった(0/10)。すなわち、実験終了時の生存率は対照群で50%、2000ppm含有飼料投与群で90%、4000ppm含有飼料投与群で100%であり、対照群と4000ppm含有飼料投与群の間に統計学的な差が観察された。 (result)
1. Survival rate The survival rate is as shown in FIG. As is apparent from this figure, 5 death cases (5/10) were observed at the 6th and 7th week in the control group, whereas one case at 7th week in the feed administration group containing the
2.一般症状、被験物質摂取量および体重
各群とも一般状態は極めて良好であり、投与に起因すると考えられる症状の発現は見られなかった。また体重1kg当たりの1日のα-マンゴスチンドデカン酸ジエステルの摂取量は2000ppm含有飼料投与群では359mg、4000ppm含有飼料投与群では735mgであった。体重の経時的な変化は図2の通りであり、対照群と投与群との間に差は認められなかった。 2. General symptoms, test substance intake, and body weight The general condition was very good in each group, and no symptoms that could be attributed to administration were observed. The daily intake of α-mangosteen dodecanoic acid diester per kg body weight was 359 mg in the feed administration group containing 2000 ppm and 735 mg in the feed administration group containing 4000 ppm. The change in body weight over time is as shown in FIG. 2, and no difference was observed between the control group and the administration group.
各群とも一般状態は極めて良好であり、投与に起因すると考えられる症状の発現は見られなかった。また体重1kg当たりの1日のα-マンゴスチンドデカン酸ジエステルの摂取量は2000ppm含有飼料投与群では359mg、4000ppm含有飼料投与群では735mgであった。体重の経時的な変化は図2の通りであり、対照群と投与群との間に差は認められなかった。 2. General symptoms, test substance intake, and body weight The general condition was very good in each group, and no symptoms that could be attributed to administration were observed. The daily intake of α-mangosteen dodecanoic acid diester per kg body weight was 359 mg in the feed administration group containing 2000 ppm and 735 mg in the feed administration group containing 4000 ppm. The change in body weight over time is as shown in FIG. 2, and no difference was observed between the control group and the administration group.
3.腫瘍体積
腫瘍体積の経時的な変化は図3の通りである。この図からわかるように、4000ppm含有飼料投与群では実験開始の1週より6週まで、対照群と比較して、腫瘍体積は有意な低値を示した。2000ppm含有飼料投与群では実験開始の5週時を除き2週より6週まで、腫瘍体積は有意な低値を示した。実験終了時では、対照群と比較して、2000ppm含有飼料投与群では26%、4000ppm含有飼料投与群では38%、腫瘍体積は小さかった。 3. Tumor Volume The change in tumor volume over time is as shown in FIG. As can be seen from this figure, in the 4000 ppm-containing feed administration group, the tumor volume was significantly lower than the control group from 1 week to 6 weeks from the start of the experiment. In the feed administration group containing 2000 ppm, the tumor volume showed a significantly low value from 2 weeks to 6 weeks except at 5 weeks from the start of the experiment. At the end of the experiment, compared to the control group, the tumor volume was 26% in the feed administration group containing 2000 ppm and 38% in the feed administration group containing 4000 ppm, and the tumor volume was small.
腫瘍体積の経時的な変化は図3の通りである。この図からわかるように、4000ppm含有飼料投与群では実験開始の1週より6週まで、対照群と比較して、腫瘍体積は有意な低値を示した。2000ppm含有飼料投与群では実験開始の5週時を除き2週より6週まで、腫瘍体積は有意な低値を示した。実験終了時では、対照群と比較して、2000ppm含有飼料投与群では26%、4000ppm含有飼料投与群では38%、腫瘍体積は小さかった。 3. Tumor Volume The change in tumor volume over time is as shown in FIG. As can be seen from this figure, in the 4000 ppm-containing feed administration group, the tumor volume was significantly lower than the control group from 1 week to 6 weeks from the start of the experiment. In the feed administration group containing 2000 ppm, the tumor volume showed a significantly low value from 2 weeks to 6 weeks except at 5 weeks from the start of the experiment. At the end of the experiment, compared to the control group, the tumor volume was 26% in the feed administration group containing 2000 ppm and 38% in the feed administration group containing 4000 ppm, and the tumor volume was small.
4.癌転移の生体イメージング
癌転移の生体イメージングの結果は図4の通りである。各図において、マウスの体内に島状に出現している腫瘍領域が、中心に寄る程強まる体内発光の強度に応じて、段階的に色分け表示されている。これらの図から分かるように、いずれの群においても、腋窩リンパ節や鼡径リンパ節への転移が観察されたが、その拡がりの程度は2000および4000ppm含有飼料投与群ともに対照群に対して明らかに軽度であった。 4). In vivo imaging of cancer metastasis The results of in vivo imaging of cancer metastasis are as shown in FIG. In each figure, the tumor region appearing in an island shape in the mouse body is displayed in different colors step by step according to the intensity of the in-vivo luminescence that becomes stronger toward the center. As can be seen from these figures, metastasis to axillary lymph nodes and inguinal lymph nodes was observed in any group, but the extent of the spread was evident in both the 2000 and 4000 ppm diet-containing groups compared to the control group. It was mild.
癌転移の生体イメージングの結果は図4の通りである。各図において、マウスの体内に島状に出現している腫瘍領域が、中心に寄る程強まる体内発光の強度に応じて、段階的に色分け表示されている。これらの図から分かるように、いずれの群においても、腋窩リンパ節や鼡径リンパ節への転移が観察されたが、その拡がりの程度は2000および4000ppm含有飼料投与群ともに対照群に対して明らかに軽度であった。 4). In vivo imaging of cancer metastasis The results of in vivo imaging of cancer metastasis are as shown in FIG. In each figure, the tumor region appearing in an island shape in the mouse body is displayed in different colors step by step according to the intensity of the in-vivo luminescence that becomes stronger toward the center. As can be seen from these figures, metastasis to axillary lymph nodes and inguinal lymph nodes was observed in any group, but the extent of the spread was evident in both the 2000 and 4000 ppm diet-containing groups compared to the control group. It was mild.
5.リンパ節転移および肺転移
マウス1匹当たりのリンパ節転移の数(転移したリンパ節の数)は、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して顕著な低下が示され、低下は統計学的にも有意であった(図5a)。肺転移では、転移巣が1mm以上のものについて、マウス1匹当たりの数を算出すると、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して極めて顕著な低下が示され、低下は統計学的にも有意であった(図5b)。なお、図5a及び図5bにおいて、数値は、各群における平均値を表し、エラーバーは標準偏差を表す(以下、同種の図において同じ)。 5. Lymph node metastasis and lung metastasis The number of lymph node metastases per mouse (the number of metastasized lymph nodes) was significantly decreased in both the 2000 ppm-containing diet group and the 4000 ppm-containing diet group compared to the control group. The decrease was also statistically significant (FIG. 5a). For lung metastases, when the number of metastases was 1 mm or more and the number per mouse was calculated, both the 2000 ppm-containing feed group and the 4000 ppm-containing feed group showed a very marked decrease compared to the control group. Was also statistically significant (FIG. 5b). In FIGS. 5a and 5b, the numerical value represents the average value in each group, and the error bar represents the standard deviation (hereinafter the same in the same kind of figures).
マウス1匹当たりのリンパ節転移の数(転移したリンパ節の数)は、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して顕著な低下が示され、低下は統計学的にも有意であった(図5a)。肺転移では、転移巣が1mm以上のものについて、マウス1匹当たりの数を算出すると、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して極めて顕著な低下が示され、低下は統計学的にも有意であった(図5b)。なお、図5a及び図5bにおいて、数値は、各群における平均値を表し、エラーバーは標準偏差を表す(以下、同種の図において同じ)。 5. Lymph node metastasis and lung metastasis The number of lymph node metastases per mouse (the number of metastasized lymph nodes) was significantly decreased in both the 2000 ppm-containing diet group and the 4000 ppm-containing diet group compared to the control group. The decrease was also statistically significant (FIG. 5a). For lung metastases, when the number of metastases was 1 mm or more and the number per mouse was calculated, both the 2000 ppm-containing feed group and the 4000 ppm-containing feed group showed a very marked decrease compared to the control group. Was also statistically significant (FIG. 5b). In FIGS. 5a and 5b, the numerical value represents the average value in each group, and the error bar represents the standard deviation (hereinafter the same in the same kind of figures).
6.転移した臓器の総数
リンパ節や肺以外にも卵巣、副腎、腎臓、肝臓、骨への転移が病理組織学的に観察された。転移した臓器の総数は、対照群で125個であったのに対し、2000ppm含有飼料投与群で48個、4000ppm含有飼料投与群で37個であり、著しく抑制されていた(図6a)。マウス1匹当たりの転移臓器数を算出すると、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して有意な低下が示された(図6b)。なお、転移した臓器の総数は、リンパ節及び肺については上記のとおりカウントし、その他の臓器については、左右ある卵巣、副腎、腎臓は片側のみの転移であれば「1」と、両側とも転移していれば「2」と、肝臓及び骨は転移があれば「1」と、それぞれカウントした。 6). Total number of organs that metastasized In addition to lymph nodes and lungs, metastasis to the ovary, adrenal gland, kidney, liver, and bone was observed histopathologically. The total number of organs that had metastasized was 125 in the control group, 48 in the feed administration group containing 2000 ppm and 37 in the feed administration group containing 4000 ppm, which was remarkably suppressed (FIG. 6a). When the number of metastatic organs per mouse was calculated, the 2000 ppm-containing feed administration group and the 4000 ppm-containing feed administration group both showed a significant decrease compared to the control group (FIG. 6b). The total number of metastasized organs is counted as above for lymph nodes and lungs, and for other organs, the left and right ovaries, adrenal glands, and kidneys are “1” if they are metastasizing only on one side, and both sides are metastasized. “2” if it was, and “1” if the liver and bone had metastasis.
リンパ節や肺以外にも卵巣、副腎、腎臓、肝臓、骨への転移が病理組織学的に観察された。転移した臓器の総数は、対照群で125個であったのに対し、2000ppm含有飼料投与群で48個、4000ppm含有飼料投与群で37個であり、著しく抑制されていた(図6a)。マウス1匹当たりの転移臓器数を算出すると、2000ppm含有飼料投与群および4000ppm含有飼料投与群でともに対照群に対して有意な低下が示された(図6b)。なお、転移した臓器の総数は、リンパ節及び肺については上記のとおりカウントし、その他の臓器については、左右ある卵巣、副腎、腎臓は片側のみの転移であれば「1」と、両側とも転移していれば「2」と、肝臓及び骨は転移があれば「1」と、それぞれカウントした。 6). Total number of organs that metastasized In addition to lymph nodes and lungs, metastasis to the ovary, adrenal gland, kidney, liver, and bone was observed histopathologically. The total number of organs that had metastasized was 125 in the control group, 48 in the feed administration group containing 2000 ppm and 37 in the feed administration group containing 4000 ppm, which was remarkably suppressed (FIG. 6a). When the number of metastatic organs per mouse was calculated, the 2000 ppm-containing feed administration group and the 4000 ppm-containing feed administration group both showed a significant decrease compared to the control group (FIG. 6b). The total number of metastasized organs is counted as above for lymph nodes and lungs, and for other organs, the left and right ovaries, adrenal glands, and kidneys are “1” if they are metastasizing only on one side, and both sides are metastasized. “2” if it was, and “1” if the liver and bone had metastasis.
[比較例1]
ルシフェラーゼを組み込んでいないBJMC細胞を移植したマウス乳癌モデルを用いて、α-マンゴスチンの乳癌実験を(実験期間は8週間)を行った。0ppm(対照群)、250ppmおよび2500ppmの濃度で、試験例1と同様に、各群10匹(合計30匹)のマウスに混餌投与を行った。
その結果、対照群および250ppm含有飼料投与群で各1例の腫瘍による死亡例を観察した。なお、2500ppm含有飼料投与群では実験開始の3週目にケージのフタに挟まれて1例の死亡を観察し、この動物については解析から除外した。体重変化では各群間に差はなく(図7)、腫瘍体積では2500ppm含有飼料投与群で4週より実験終了の8週まで有意な抑制が観察された(図8)。マウス1匹当たりのリンパ節転移の個数を見ると(図9a)、2500ppm含有飼料投与群で抑制傾向は認められるものの統計学的な有意差は示されなかった。また、肺転移巣が1mm以上のものについて、マウス1匹当たりの転移巣の個数を解析すると、逆に2500ppm含有飼料投与群で増加傾向が示された(図9b)。 [Comparative Example 1]
Using a mouse breast cancer model transplanted with BJMC cells not incorporating luciferase, a breast cancer experiment for α-mangosteen was conducted (experiment period was 8 weeks). In the same manner as in Test Example 1, 10 mice in each group (total of 30 mice) were fed at a concentration of 0 ppm (control group), 250 ppm and 2500 ppm.
As a result, one death case due to tumor was observed in each of the control group and the feed administration group containing 250 ppm. In the feed administration group containing 2500 ppm, one death was observed by being caught in the cage lid on the third week after the start of the experiment, and this animal was excluded from the analysis. There was no difference between the groups in the change in body weight (FIG. 7), and in the tumor volume, a significant suppression was observed from 4 weeks in the feed administration group containing 2500 ppm to 8 weeks after the end of the experiment (FIG. 8). When looking at the number of lymph node metastases per mouse (FIG. 9a), although a suppression tendency was observed in the 2500 ppm-containing feed group, no statistically significant difference was shown. Moreover, when the number of metastatic foci per mouse was analyzed for lung metastases of 1 mm or more, conversely, an increasing trend was shown in the feed administration group containing 2500 ppm (FIG. 9b).
ルシフェラーゼを組み込んでいないBJMC細胞を移植したマウス乳癌モデルを用いて、α-マンゴスチンの乳癌実験を(実験期間は8週間)を行った。0ppm(対照群)、250ppmおよび2500ppmの濃度で、試験例1と同様に、各群10匹(合計30匹)のマウスに混餌投与を行った。
その結果、対照群および250ppm含有飼料投与群で各1例の腫瘍による死亡例を観察した。なお、2500ppm含有飼料投与群では実験開始の3週目にケージのフタに挟まれて1例の死亡を観察し、この動物については解析から除外した。体重変化では各群間に差はなく(図7)、腫瘍体積では2500ppm含有飼料投与群で4週より実験終了の8週まで有意な抑制が観察された(図8)。マウス1匹当たりのリンパ節転移の個数を見ると(図9a)、2500ppm含有飼料投与群で抑制傾向は認められるものの統計学的な有意差は示されなかった。また、肺転移巣が1mm以上のものについて、マウス1匹当たりの転移巣の個数を解析すると、逆に2500ppm含有飼料投与群で増加傾向が示された(図9b)。 [Comparative Example 1]
Using a mouse breast cancer model transplanted with BJMC cells not incorporating luciferase, a breast cancer experiment for α-mangosteen was conducted (experiment period was 8 weeks). In the same manner as in Test Example 1, 10 mice in each group (total of 30 mice) were fed at a concentration of 0 ppm (control group), 250 ppm and 2500 ppm.
As a result, one death case due to tumor was observed in each of the control group and the feed administration group containing 250 ppm. In the feed administration group containing 2500 ppm, one death was observed by being caught in the cage lid on the third week after the start of the experiment, and this animal was excluded from the analysis. There was no difference between the groups in the change in body weight (FIG. 7), and in the tumor volume, a significant suppression was observed from 4 weeks in the feed administration group containing 2500 ppm to 8 weeks after the end of the experiment (FIG. 8). When looking at the number of lymph node metastases per mouse (FIG. 9a), although a suppression tendency was observed in the 2500 ppm-containing feed group, no statistically significant difference was shown. Moreover, when the number of metastatic foci per mouse was analyzed for lung metastases of 1 mm or more, conversely, an increasing trend was shown in the feed administration group containing 2500 ppm (FIG. 9b).
[考察]
試験例1と比較例1との結果から、α-マンゴスチンドデカン酸ジエステルを含む本発明の化合物(1)はα-マンゴスチンに比べて、顕著に優れた癌転移抑制作用を有していることが分かる。 [Discussion]
From the results of Test Example 1 and Comparative Example 1, it can be seen that the compound (1) of the present invention containing α-mangosteen dodecanoic acid diester has a markedly superior cancer metastasis inhibitory action compared to α-mangostin. I understand.
試験例1と比較例1との結果から、α-マンゴスチンドデカン酸ジエステルを含む本発明の化合物(1)はα-マンゴスチンに比べて、顕著に優れた癌転移抑制作用を有していることが分かる。 [Discussion]
From the results of Test Example 1 and Comparative Example 1, it can be seen that the compound (1) of the present invention containing α-mangosteen dodecanoic acid diester has a markedly superior cancer metastasis inhibitory action compared to α-mangostin. I understand.
[実施例1]
(α-マンゴスチンドデカン酸ジエステルの合成) [Example 1]
(Synthesis of α-mangosteen dodecanoic acid diester)
(α-マンゴスチンドデカン酸ジエステルの合成) [Example 1]
(Synthesis of α-mangosteen dodecanoic acid diester)
ドデカン酸(C12)(5g、0.25mol、和光純薬工業社)を塩化チオニル(7ml、和光純薬工業社)と共に水浴上で2時間還流し、その後、過剰な塩化チオニルは減圧下に留去しドデカン酸クロリドを調製した。α-マンゴスチン(4.1g、0.01mol)をピリジン(3ml)およびテトロヒドロフラン(30ml)に溶かし、この溶液をドデカン酸クロリドの中に滴下した。反応液を水浴上で加温(3時間)し、冷後1N塩酸(50ml)に加え、酢酸エチルで抽出した。抽出液を濃縮後、シリカゲルカラムクロマトグラフィー(流出液:クロロホルム)に付して、精製し、α-マンゴスチンドデカン酸ジエステル(=α-マンゴスチンラウリル酸ジエステル)(6.5g)を淡黄色油状物として得た。
(本品の物理恒数)
融点:39-40℃(室温で淡黄色アモルファスとして固化)
分子式:C48H70O8
分子量:774
EIMS m/z (%): 774 (M+, 100), 718 (6), 592 (70), 536 (28), 409 (34), 367 (36), 354 (64), 339 (99), 323 (24), 311 (20), 183 (19), 71 (26), 57 (60).
1H-NMR (400 MHz, CDCl3) δ: 0.87, 0.89 (3H each, d, J= 6.9 Hz, dodecanoate-H-12’and H-12”), 1.26 (36H, m, dodecanoate-H-3’-H-11’and H-3”-H-11”), 1.43 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.59, 2.63 (2H each, t, J= 7.5 Hz, dodecanoate-H-2’and H-2”), 3.30 (2H, s, J= 5.5 Hz, H-11), 3.76 (3H, s, OMe-C-7), 4.13 (2H, d, J= 5.0 Hz, H-16), 5.14, 5.19 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). Dodecanoic acid (C 12 ) (5 g, 0.25 mol, Wako Pure Chemical Industries) was refluxed with thionyl chloride (7 ml, Wako Pure Chemical Industries) on a water bath for 2 hours, after which excess thionyl chloride was removed under reduced pressure. Distilled off to prepare dodecanoic acid chloride. α-Mangosteen (4.1 g, 0.01 mol) was dissolved in pyridine (3 ml) and tetrohydrofuran (30 ml), and this solution was added dropwise into dodecanoic acid chloride. The reaction solution was heated on a water bath (3 hours), cooled, added to 1N hydrochloric acid (50 ml), and extracted with ethyl acetate. The extract was concentrated, purified by silica gel column chromatography (eluent: chloroform), and α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) (6.5 g) as a pale yellow oil. Obtained.
(Physical constant of this product)
Melting point: 39-40 ° C (solidifies as light yellow amorphous at room temperature)
Molecular formula: C 48 H 70 O 8
Molecular weight: 774
EIMS m / z (%): 774 (M + , 100), 718 (6), 592 (70), 536 (28), 409 (34), 367 (36), 354 (64), 339 (99) , 323 (24), 311 (20), 183 (19), 71 (26), 57 (60).
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87, 0.89 (3H each, d, J = 6.9 Hz, dodecanoate-H-12'and H-12 ”), 1.26 (36H, m, dodecanoate-H- 3'-H-11'and H-3 ”-H-11”), 1.43 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20 ), 2.59, 2.63 (2H each, t, J = 7.5 Hz, dodecanoate-H-2'and H-2 ”), 3.30 (2H, s, J = 5.5 Hz, H-11), 3.76 (3H, s , OMe-C-7), 4.13 (2H, d, J = 5.0 Hz, H-16), 5.14, 5.19 (1H each, m, H-12 and H-17), 6.62 (1H, s, H- 4), 7.11 (1H, s, H-5).
(本品の物理恒数)
融点:39-40℃(室温で淡黄色アモルファスとして固化)
分子式:C48H70O8
分子量:774
EIMS m/z (%): 774 (M+, 100), 718 (6), 592 (70), 536 (28), 409 (34), 367 (36), 354 (64), 339 (99), 323 (24), 311 (20), 183 (19), 71 (26), 57 (60).
1H-NMR (400 MHz, CDCl3) δ: 0.87, 0.89 (3H each, d, J= 6.9 Hz, dodecanoate-H-12’and H-12”), 1.26 (36H, m, dodecanoate-H-3’-H-11’and H-3”-H-11”), 1.43 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.59, 2.63 (2H each, t, J= 7.5 Hz, dodecanoate-H-2’and H-2”), 3.30 (2H, s, J= 5.5 Hz, H-11), 3.76 (3H, s, OMe-C-7), 4.13 (2H, d, J= 5.0 Hz, H-16), 5.14, 5.19 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). Dodecanoic acid (C 12 ) (5 g, 0.25 mol, Wako Pure Chemical Industries) was refluxed with thionyl chloride (7 ml, Wako Pure Chemical Industries) on a water bath for 2 hours, after which excess thionyl chloride was removed under reduced pressure. Distilled off to prepare dodecanoic acid chloride. α-Mangosteen (4.1 g, 0.01 mol) was dissolved in pyridine (3 ml) and tetrohydrofuran (30 ml), and this solution was added dropwise into dodecanoic acid chloride. The reaction solution was heated on a water bath (3 hours), cooled, added to 1N hydrochloric acid (50 ml), and extracted with ethyl acetate. The extract was concentrated, purified by silica gel column chromatography (eluent: chloroform), and α-mangosteen dodecanoic acid diester (= α-mangosteen lauric acid diester) (6.5 g) as a pale yellow oil. Obtained.
(Physical constant of this product)
Melting point: 39-40 ° C (solidifies as light yellow amorphous at room temperature)
Molecular formula: C 48 H 70 O 8
Molecular weight: 774
EIMS m / z (%): 774 (M + , 100), 718 (6), 592 (70), 536 (28), 409 (34), 367 (36), 354 (64), 339 (99) , 323 (24), 311 (20), 183 (19), 71 (26), 57 (60).
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87, 0.89 (3H each, d, J = 6.9 Hz, dodecanoate-H-12'and H-12 ”), 1.26 (36H, m, dodecanoate-H- 3'-H-11'and H-3 ”-H-11”), 1.43 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20 ), 2.59, 2.63 (2H each, t, J = 7.5 Hz, dodecanoate-H-2'and H-2 ”), 3.30 (2H, s, J = 5.5 Hz, H-11), 3.76 (3H, s , OMe-C-7), 4.13 (2H, d, J = 5.0 Hz, H-16), 5.14, 5.19 (1H each, m, H-12 and H-17), 6.62 (1H, s, H- 4), 7.11 (1H, s, H-5).
[実施例2]
(α-マンゴスチンデカン酸ジエステルの合成) [Example 2]
(Synthesis of α-mangosteen decanoic acid diester)
(α-マンゴスチンデカン酸ジエステルの合成) [Example 2]
(Synthesis of α-mangosteen decanoic acid diester)
ドデカン酸の代わりにデカン酸(C10)を用いる以外は、実施例1と同様に処理して、α-マンゴスチンデカン酸ジエステル(=α-マンゴスチンカプリン酸ジエステル)を褐色油状物として得た。
(本品の物理恒数)
分子式:C44H62O8
分子量:718
EIMS m/z (%): 718 (M+, 100), 662 (7), 564 (16), 508 (22), 409 (12), 355 (18), 339 (29), 325 (8).
1H-NMR (400 MHz, CDCl3) δ: 0.88, 0.89 (3H each, d, J= 6.9 Hz, decanoate-H-10’and H-10”), 1.29-1.31 (28H, m, decanoate-H-3’-H-9’and H-3”-H-9”), 1.68 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.59, 2.63 (2H each, t, J= 7.5 Hz, decanoate-H-2’and H-2”), 3.30 (2H, d, J= 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J= 6.3 Hz, H-16), 5.14, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). Except for using decanoic acid (C 10 ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen decanoic acid diester (= α-mangosteen capric acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C 44 H 62 O 8
Molecular weight: 718
EIMS m / z (%): 718 (M + , 100), 662 (7), 564 (16), 508 (22), 409 (12), 355 (18), 339 (29), 325 (8) .
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88, 0.89 (3H each, d, J = 6.9 Hz, decanoate-H-10'and H-10 ”), 1.29-1.31 (28H, m, decanoate- H-3'-H-9'and H-3 ”-H-9”), 1.68 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H -20), 2.59, 2.63 (2H each, t, J = 7.5 Hz, decanoate-H-2'and H-2 ”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H , s, OMe-C-7), 4.13 (2H, d, J = 6.3 Hz, H-16), 5.14, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
(本品の物理恒数)
分子式:C44H62O8
分子量:718
EIMS m/z (%): 718 (M+, 100), 662 (7), 564 (16), 508 (22), 409 (12), 355 (18), 339 (29), 325 (8).
1H-NMR (400 MHz, CDCl3) δ: 0.88, 0.89 (3H each, d, J= 6.9 Hz, decanoate-H-10’and H-10”), 1.29-1.31 (28H, m, decanoate-H-3’-H-9’and H-3”-H-9”), 1.68 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.59, 2.63 (2H each, t, J= 7.5 Hz, decanoate-H-2’and H-2”), 3.30 (2H, d, J= 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J= 6.3 Hz, H-16), 5.14, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). Except for using decanoic acid (C 10 ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen decanoic acid diester (= α-mangosteen capric acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C 44 H 62 O 8
Molecular weight: 718
EIMS m / z (%): 718 (M + , 100), 662 (7), 564 (16), 508 (22), 409 (12), 355 (18), 339 (29), 325 (8) .
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.88, 0.89 (3H each, d, J = 6.9 Hz, decanoate-H-10'and H-10 ”), 1.29-1.31 (28H, m, decanoate- H-3'-H-9'and H-3 ”-H-9”), 1.68 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H -20), 2.59, 2.63 (2H each, t, J = 7.5 Hz, decanoate-H-2'and H-2 ”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H , s, OMe-C-7), 4.13 (2H, d, J = 6.3 Hz, H-16), 5.14, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
[実施例3]
(α-マンゴスチン10-ウンデセン酸ジエステルの合成) [Example 3]
(Synthesis of α-Mangosteen 10-Undecenoic Acid Diester)
(α-マンゴスチン10-ウンデセン酸ジエステルの合成) [Example 3]
(Synthesis of α-Mangosteen 10-Undecenoic Acid Diester)
ドデカン酸の代わりに10-ウンデセン酸(C11)を用いる以外は、実施例1と同様に処理して、α-マンゴスチン10-ウンデセン酸ジエステルを淡黄色褐油状物として得た。
(本品の物理恒数)
分子式:C46H62O8
分子量:742
EIMS m/z (%): 742 (M+, 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72), 325 (15).
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.40 (24H, m, undecenoate-H-3’-H-8’and H-3”-H-8”), 1.67 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.04, 2.06 (2H each, m, undecenoate-H-9’and H-9”), 2.60, 2.64 (2H each, t, J= 7.5 Hz, undecenoate-H-2’and H-2”), 3.30 (1H, d, J= 6.8 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (1H, d, J= 6.3 Hz, H-16), 4.93 (2H, d, J= 10.3 Hz, undecenoate-H-11’a and H-11”a), 5.00 (2H, d, J= 17.2 Hz, undecenoate-H-11’b and H-11”b), 5.14, 5.19 (1H each, m, H-12 and H-17), 5.82 (2H, m, undecenoate-H-10’and H-10”), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). The same treatment as in Example 1 was carried out except that 10-undecenoic acid (C 11 ) was used instead of dodecanoic acid to obtain α-mangostin 10-undecenoic acid diester as a pale yellow brown oily substance.
(Physical constant of this product)
Molecular formula: C 46 H 62 O 8
Molecular weight: 742
EIMS m / z (%): 742 (M + , 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72) , 325 (15).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.32-1.40 (24H, m, undecenoate-H-3'-H-8'and H-3 ”-H-8”), 1.67 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.04, 2.06 (2H each, m, undecenoate-H-9'and H-9 ”), 2.60 , 2.64 (2H each, t, J = 7.5 Hz, undecenoate-H-2'and H-2 ”), 3.30 (1H, d, J = 6.8 Hz, H-11), 3.75 (3H, s, OMe- C-7), 4.13 (1H, d, J = 6.3 Hz, H-16), 4.93 (2H, d, J = 10.3 Hz, undecenoate-H-11'a and H-11 ”a), 5.00 (2H , d, J = 17.2 Hz, undecenoate-H-11'b and H-11 ”b), 5.14, 5.19 (1H each, m, H-12 and H-17), 5.82 (2H, m, undecenoate-H -10'and H-10 "), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
(本品の物理恒数)
分子式:C46H62O8
分子量:742
EIMS m/z (%): 742 (M+, 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72), 325 (15).
1H-NMR (400 MHz, CDCl3) δ: 1.32-1.40 (24H, m, undecenoate-H-3’-H-8’and H-3”-H-8”), 1.67 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.04, 2.06 (2H each, m, undecenoate-H-9’and H-9”), 2.60, 2.64 (2H each, t, J= 7.5 Hz, undecenoate-H-2’and H-2”), 3.30 (1H, d, J= 6.8 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (1H, d, J= 6.3 Hz, H-16), 4.93 (2H, d, J= 10.3 Hz, undecenoate-H-11’a and H-11”a), 5.00 (2H, d, J= 17.2 Hz, undecenoate-H-11’b and H-11”b), 5.14, 5.19 (1H each, m, H-12 and H-17), 5.82 (2H, m, undecenoate-H-10’and H-10”), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5). The same treatment as in Example 1 was carried out except that 10-undecenoic acid (C 11 ) was used instead of dodecanoic acid to obtain α-mangostin 10-undecenoic acid diester as a pale yellow brown oily substance.
(Physical constant of this product)
Molecular formula: C 46 H 62 O 8
Molecular weight: 742
EIMS m / z (%): 742 (M + , 100), 730 (18), 576 (56), 533 (12), 520 (35), 409 (23), 355 (55), 339 (72) , 325 (15).
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.32-1.40 (24H, m, undecenoate-H-3'-H-8'and H-3 ”-H-8”), 1.67 (6H, s, H-14, H-15), 1.77, 1.83 (3H each, s, H-19 and H-20), 2.04, 2.06 (2H each, m, undecenoate-H-9'and H-9 ”), 2.60 , 2.64 (2H each, t, J = 7.5 Hz, undecenoate-H-2'and H-2 ”), 3.30 (1H, d, J = 6.8 Hz, H-11), 3.75 (3H, s, OMe- C-7), 4.13 (1H, d, J = 6.3 Hz, H-16), 4.93 (2H, d, J = 10.3 Hz, undecenoate-H-11'a and H-11 ”a), 5.00 (2H , d, J = 17.2 Hz, undecenoate-H-11'b and H-11 ”b), 5.14, 5.19 (1H each, m, H-12 and H-17), 5.82 (2H, m, undecenoate-H -10'and H-10 "), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
[実施例4]
(α-マンゴスチンオクタン酸ジエステルの合成) [Example 4]
(Synthesis of α-mangosteen octanoic acid diester)
(α-マンゴスチンオクタン酸ジエステルの合成) [Example 4]
(Synthesis of α-mangosteen octanoic acid diester)
ドデカン酸の代わりにオクタン酸(C8)を用いる以外は、実施例1と同様に処理して、α-マンゴスチンオクタン酸ジエステル(=α-マンゴスチンカプリル酸ジエステル)を褐色油状物として得た。
(本品の物理恒数)
分子式:C40H54O8
分子量:662
negative HR ESI-TOFMS m/z : 661.3726 [M-H]-, calcd. 661.3746.
negative ESI-TOFMS m/z (%): 661 (21), 535 (100), 395 (10), 281 (49), 265 (82), 255 (37), 182 (25).
1H-NMR (400 MHz, CDCl3) δ: 0.90 (6H each, d, J= 7.1 Hz, octanoate-H-8’and H-8”), 1.27-1.45 (16H, m, octanoate-H-4’-H-7’and H-4”-H-7”), 1.43, 1.69, 1.77, 1.89 (3H each s, CH3-C-14,15,19,20) , 1.78, 1.80 (2H each, m, octanoate-H-3’and H-3”), 2.59, 2.64 (2H each, t, J= 7.5 Hz, octanoate-H-2’and H-2”), 3.30 (2H, d, J= 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J= 6.5 Hz, H-16), 5.15, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
13C-NMR (125 MHz, CDCl3) δ: 12.6 (C-8’, C-8”), 16.4, 16.7 (C-15, C-19), 20.8 (C-11), 21.1 (C-5’, C-5”), 23.31, 23.34 (C-3’, C-3”), 24.4, 24.3 (C-6’, C-6”), 25.0 (C-16), 27.42, 27.44, 27.5, 27.6 (C-4’, C-5’, C-4”, C-5”), 30.1 (C-6’, C-6”), 32.7, 32.8 (C-2’, C-2”), 60.2 (OMe -C-7), 98.8 (C-4), 105.5 (C-9a), 109.1 (C-5), 114.7, 115.2 (C-2, C-8a), 119.9, 121.2 (C12, C-17), 130.7 (C-8, C-13), 137.5 (C-18), 145.3 (C-7), 148.0 (C-6), 152.2, 152.6, 153.5 (C-1, C-3, C-4a), 159.5 (C-10a), 169.4, 169.8 (C-1’, C-1”), 181.6 (C-9). Except for using octanoic acid (C 8 ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen octanoic acid diester (= α-mangosteen caprylic acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C 40 H 54 O 8
Molecular weight: 662
negative HR ESI-TOFMS m / z: 661.3726 [MH] - , calcd. 661.3746.
negative ESI-TOFMS m / z (%): 661 (21), 535 (100), 395 (10), 281 (49), 265 (82), 255 (37), 182 (25).
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (6H each, d, J = 7.1 Hz, octanoate-H-8'and H-8 ”), 1.27-1.45 (16H, m, octanoate-H- 4'-H-7'and H-4 ”-H-7”), 1.43, 1.69, 1.77, 1.89 (3H each s, CH 3 -C-14,15,19,20), 1.78, 1.80 (2H each, m, octanoate-H-3'and H-3 ”), 2.59, 2.64 (2H each, t, J = 7.5 Hz, octanoate-H-2'and H-2”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J = 6.5 Hz, H-16), 5.15, 5.20 (1H each, m, H- 12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
13 C-NMR (125 MHz, CDCl 3 ) δ: 12.6 (C-8 ', C-8 ”), 16.4, 16.7 (C-15, C-19), 20.8 (C-11), 21.1 (C- 5 ', C-5 "), 23.31, 23.34 (C-3', C-3"), 24.4, 24.3 (C-6 ', C-6 "), 25.0 (C-16), 27.42, 27.44, 27.5, 27.6 (C-4 ', C-5', C-4 ", C-5"), 30.1 (C-6 ', C-6 "), 32.7, 32.8 (C-2', C-2 ''), 60.2 (OMe -C-7), 98.8 (C-4), 105.5 (C-9a), 109.1 (C-5), 114.7, 115.2 (C-2, C-8a), 119.9, 121.2 ( C12, C-17), 130.7 (C-8, C-13), 137.5 (C-18), 145.3 (C-7), 148.0 (C-6), 152.2, 152.6, 153.5 (C-1, C -3, C-4a), 159.5 (C-10a), 169.4, 169.8 (C-1 ', C-1''), 181.6 (C-9).
(本品の物理恒数)
分子式:C40H54O8
分子量:662
negative HR ESI-TOFMS m/z : 661.3726 [M-H]-, calcd. 661.3746.
negative ESI-TOFMS m/z (%): 661 (21), 535 (100), 395 (10), 281 (49), 265 (82), 255 (37), 182 (25).
1H-NMR (400 MHz, CDCl3) δ: 0.90 (6H each, d, J= 7.1 Hz, octanoate-H-8’and H-8”), 1.27-1.45 (16H, m, octanoate-H-4’-H-7’and H-4”-H-7”), 1.43, 1.69, 1.77, 1.89 (3H each s, CH3-C-14,15,19,20) , 1.78, 1.80 (2H each, m, octanoate-H-3’and H-3”), 2.59, 2.64 (2H each, t, J= 7.5 Hz, octanoate-H-2’and H-2”), 3.30 (2H, d, J= 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J= 6.5 Hz, H-16), 5.15, 5.20 (1H each, m, H-12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
13C-NMR (125 MHz, CDCl3) δ: 12.6 (C-8’, C-8”), 16.4, 16.7 (C-15, C-19), 20.8 (C-11), 21.1 (C-5’, C-5”), 23.31, 23.34 (C-3’, C-3”), 24.4, 24.3 (C-6’, C-6”), 25.0 (C-16), 27.42, 27.44, 27.5, 27.6 (C-4’, C-5’, C-4”, C-5”), 30.1 (C-6’, C-6”), 32.7, 32.8 (C-2’, C-2”), 60.2 (OMe -C-7), 98.8 (C-4), 105.5 (C-9a), 109.1 (C-5), 114.7, 115.2 (C-2, C-8a), 119.9, 121.2 (C12, C-17), 130.7 (C-8, C-13), 137.5 (C-18), 145.3 (C-7), 148.0 (C-6), 152.2, 152.6, 153.5 (C-1, C-3, C-4a), 159.5 (C-10a), 169.4, 169.8 (C-1’, C-1”), 181.6 (C-9). Except for using octanoic acid (C 8 ) in place of dodecanoic acid, the same treatment as in Example 1 was carried out to obtain α-mangosteen octanoic acid diester (= α-mangosteen caprylic acid diester) as a brown oil.
(Physical constant of this product)
Molecular formula: C 40 H 54 O 8
Molecular weight: 662
negative HR ESI-TOFMS m / z: 661.3726 [MH] - , calcd. 661.3746.
negative ESI-TOFMS m / z (%): 661 (21), 535 (100), 395 (10), 281 (49), 265 (82), 255 (37), 182 (25).
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (6H each, d, J = 7.1 Hz, octanoate-H-8'and H-8 ”), 1.27-1.45 (16H, m, octanoate-H- 4'-H-7'and H-4 ”-H-7”), 1.43, 1.69, 1.77, 1.89 (3H each s, CH 3 -C-14,15,19,20), 1.78, 1.80 (2H each, m, octanoate-H-3'and H-3 ”), 2.59, 2.64 (2H each, t, J = 7.5 Hz, octanoate-H-2'and H-2”), 3.30 (2H, d, J = 6.9 Hz, H-11), 3.75 (3H, s, OMe-C-7), 4.13 (2H, d, J = 6.5 Hz, H-16), 5.15, 5.20 (1H each, m, H- 12 and H-17), 6.62 (1H, s, H-4), 7.11 (1H, s, H-5).
13 C-NMR (125 MHz, CDCl 3 ) δ: 12.6 (C-8 ', C-8 ”), 16.4, 16.7 (C-15, C-19), 20.8 (C-11), 21.1 (C- 5 ', C-5 "), 23.31, 23.34 (C-3', C-3"), 24.4, 24.3 (C-6 ', C-6 "), 25.0 (C-16), 27.42, 27.44, 27.5, 27.6 (C-4 ', C-5', C-4 ", C-5"), 30.1 (C-6 ', C-6 "), 32.7, 32.8 (C-2', C-2 ''), 60.2 (OMe -C-7), 98.8 (C-4), 105.5 (C-9a), 109.1 (C-5), 114.7, 115.2 (C-2, C-8a), 119.9, 121.2 ( C12, C-17), 130.7 (C-8, C-13), 137.5 (C-18), 145.3 (C-7), 148.0 (C-6), 152.2, 152.6, 153.5 (C-1, C -3, C-4a), 159.5 (C-10a), 169.4, 169.8 (C-1 ', C-1''), 181.6 (C-9).
[実施例5]
(α-マンゴスチンテトラデカン酸ジエステルの合成)
ドデカン酸の代わりにテトラデカン酸(C14)を用いる以外は、実施例1と同様に処理して、α-マンゴスチンテトラデカン酸ジエステル(=α-マンゴスチンミリスチン酸ジエステル)を得る。 [Example 5]
(Synthesis of α-mangosteen tetradecanoic acid diester)
An α-mangosteen tetradecanoic acid diester (= α-mangosteen myristic acid diester) is obtained in the same manner as in Example 1 except that tetradecanoic acid (C 14 ) is used instead of dodecanoic acid.
(α-マンゴスチンテトラデカン酸ジエステルの合成)
ドデカン酸の代わりにテトラデカン酸(C14)を用いる以外は、実施例1と同様に処理して、α-マンゴスチンテトラデカン酸ジエステル(=α-マンゴスチンミリスチン酸ジエステル)を得る。 [Example 5]
(Synthesis of α-mangosteen tetradecanoic acid diester)
An α-mangosteen tetradecanoic acid diester (= α-mangosteen myristic acid diester) is obtained in the same manner as in Example 1 except that tetradecanoic acid (C 14 ) is used instead of dodecanoic acid.
本発明の化合物(1)は、優れた抗癌作用および癌転移抑制作用を有するので、医薬および癌治療分野で利用できる。
Since the compound (1) of the present invention has an excellent anticancer activity and cancer metastasis inhibiting activity, it can be used in the fields of medicine and cancer treatment.
Claims (8)
- R1が炭素数8~14の飽和中鎖脂肪酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル。 The α-mangosteen diester according to claim 1, wherein R 1 is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid having 8 to 14 carbon atoms.
- R1が炭素数8~14の不飽和中鎖脂肪酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル。 The α-mangosteen diester according to claim 1, wherein R 1 is a residue obtained by removing a hydroxyl group from an unsaturated medium chain fatty acid having 8 to 14 carbon atoms.
- R1がオクタン酸、ノナン酸、デカン酸、ウンデカン酸、ドデカン酸、トリデカン酸、テトラデカン酸から選ばれる飽和中鎖脂肪酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル。 2. The α-mangosteen diester according to claim 1, wherein R 1 is a residue obtained by removing a hydroxyl group from a saturated medium chain fatty acid selected from octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid and tetradecanoic acid.
- R1が10-ウンデセン酸から水酸基を除いた残基である請求項1記載のα-マンゴスチンジエステル。 The α-mangosteen diester according to claim 1, wherein R 1 is a residue obtained by removing a hydroxyl group from 10-undecenoic acid.
- 請求項1~6のいずれかのα-マンゴスチンジエステルを有効成分として含有する抗癌剤。 An anticancer agent comprising the α-mangosteen diester according to any one of claims 1 to 6 as an active ingredient.
- 請求項1~6のいずれかのα-マンゴスチンジエステルを有効成分として含有する癌転移抑制剤。 A cancer metastasis inhibitor comprising the α-mangosteen diester according to any one of claims 1 to 6 as an active ingredient.
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CN102827151A (en) * | 2012-09-14 | 2012-12-19 | 吉林农业大学 | 7-methoxy-2, 8-bis (3-methylbut-2-enyl) xanthone-1, 3, 6-triyl tripyrazine-2-carboxylate, and semi-synthesis method and medicinal application thereof |
CN103159729A (en) * | 2012-10-22 | 2013-06-19 | 南昌大学 | Alpha-, gamma-mangostin derivative and application in anti-cancer drug preparation thereof |
CN105481819A (en) * | 2015-12-25 | 2016-04-13 | 成都普瑞法科技开发有限公司 | Alpha-mangostin derivative and application thereof in preparation of metabolic syndrome resistant medicine |
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JPWO2004066994A1 (en) * | 2003-01-28 | 2006-05-18 | 関西ティー・エル・オー株式会社 | Anticancer drug |
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WO2003057141A2 (en) * | 2001-12-27 | 2003-07-17 | Avon Products, Inc. | Methods for improving the aesthetic appearance of skin |
JP2009013105A (en) * | 2007-07-04 | 2009-01-22 | Yoshihiro Futamura | Xanthone derivatives having collagen-increasing action, method for producing the same, cosmetics and food preparation comprising the derivatives |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102827151A (en) * | 2012-09-14 | 2012-12-19 | 吉林农业大学 | 7-methoxy-2, 8-bis (3-methylbut-2-enyl) xanthone-1, 3, 6-triyl tripyrazine-2-carboxylate, and semi-synthesis method and medicinal application thereof |
CN103159729A (en) * | 2012-10-22 | 2013-06-19 | 南昌大学 | Alpha-, gamma-mangostin derivative and application in anti-cancer drug preparation thereof |
CN105481819A (en) * | 2015-12-25 | 2016-04-13 | 成都普瑞法科技开发有限公司 | Alpha-mangostin derivative and application thereof in preparation of metabolic syndrome resistant medicine |
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