CN112933077B - Use of phloroglucinol derivatives for the treatment and/or prevention of cancer - Google Patents
Use of phloroglucinol derivatives for the treatment and/or prevention of cancer Download PDFInfo
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Abstract
The invention belongs to the field of biomedicine, and relates to application of phloroglucinol derivatives in preparing a medicament for treating and/or preventing cancers, wherein the phloroglucinol derivatives are separated from black ink Eugenia jambolana Lam seeds by a phytochemical means and can be used for preparing medicaments for treating breast cancer, lung cancer, gastric cancer, colon cancer, cervical cancer, brain tumor and bladder cancer. The phloroglucinol derivative can obviously inhibit the growth of tumor cells in vitro and in vivo and is used as a potential medicament for treating or preventing cancers.
Description
Technical Field
The invention belongs to the field of biomedicine, relates to application of phloroglucinol derivatives in preparation of medicines for treating and/or preventing cancers, and more particularly relates to application of phloroglucinol derivatives in preparation of medicines for treating and/or preventing cancers, wherein the phloroglucinol derivatives are 12 phloroglucinol derivatives separated from black ink [ Eugenia jambolana Lam ] seeds by a phytochemical means, and the compounds are applied to the clinical prevention and treatment of cancers.
Background
The incidence of breast cancer is gradually increased year by year in recent years, and is the first incidence of female malignant tumors worldwide. Breast cancers are largely classified into four subtypes according to the states of endocrine receptors (estrogen receptor ER and progesterone receptor PR) and human epidermal growth factor receptor-2 (HER 2). Triple Negative Breast Cancer (TNBC), a subtype of breast cancer in which ER, PR and HER2 expression are negative, accounts for 10.0% to 20.8% of all breast cancer pathological types. TNBC has the characteristics of strong invasiveness and high recurrence, so that the subtype patient is difficult to clinically treat, has poor prognosis and has high mortality. There is currently no mature targeted therapy, surgery in combination with systemic chemotherapy being the primary treatment for this cancer. However, the current chemotherapy drugs have severe toxicity reactions, are not tolerated by some patients, and rapidly recur to metastasis once resistant. The development of efficient and low-toxicity targeted therapeutic drugs for resisting breast cancer, particularly triple negative breast cancer, is an important measure in the prevention and treatment of breast cancer.
Black Chinese ink (Eugenia jabolana Lam.) also called Hainan syzygium cumini and Wu-guan-head is a plant of Syzygium genus of Myrtaceae, and mostly grows in tropical and southern subtropical regions. Mainly produced in India, and is distributed in Fujian, yunnan, guangxi, hainan and Taiwan in China. Black ink seed has been used worldwide for the treatment of diabetes for over a century. At present, the black ink seeds are proved to have good effects of resisting diabetes and reducing blood sugar from different levels of in vitro, animal and human clinical experiments and the like. In the process of researching active ingredients in the black ink seeds, the inventor finds that part of the phloroglucinol ingredients have better anti-tumor activity, and particularly have stronger inhibiting effect on triple negative breast cancer cells MDA-MB-231.
The antitumor activity of the compound related to the invention is found for the first time.
Disclosure of Invention
The invention relates to an acyl phloroglucinol derivative with a fat side chain, which is extracted and separated from black ink (Eugenia jabolana Lam.) seeds.
In a first aspect, the present invention provides the use of a phloroglucinol derivative for the preparation of a medicament for the treatment and/or prevention of cancer.
Wherein the cancer is selected from brain, lung, liver, stomach, oral, head and neck, intestinal or rectal, colon, kidney, esophageal squamous cell, thyroid, bone, skin, non-small cell lung, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder, ovarian, peritoneal, pancreatic, breast, uterine, cervical, endometrial, prostate, female genital tract, testicular, gastrointestinal stromal, or prostate tumors.
In some preferred embodiments, the cancer is selected from the group consisting of breast cancer, liver cancer, lung cancer, gastric cancer, colon cancer, cervical cancer, brain tumor, and bladder cancer.
In some more preferred embodiments, the breast cancer is a triple negative breast cancer.
In some more preferred embodiments, the lung cancer is non-small cell lung cancer.
In some more preferred embodiments, the brain tumor is neuroblastoma.
In some preferred embodiments, the cancer is a cancer in a mammal, preferably, the mammal is a human.
In some embodiments, the phloroglucinol derivatives have the following general structural formula I:
wherein: r 1 Is methyl or hydrogen, R 2 Is methyl or hydrogen, R 1 And R 2 May be the same or different; r 3 Is alkane containing 12 to 26 carbon atoms or alkene side chain containing 1 to 2 double bonds and 12 to 26 carbon atoms.
Further, in the structural general formula I, R 1 Is methyl or hydrogen, R 2 Is methyl or hydrogen, R 1 And R 2 The same or different; r 3 Is an alkane side chain containing 15 to 17 carbons.
Further, in the structural general formula I, R 1 Is methyl or hydrogen, R 2 Is methyl or hydrogen, R 1 And R 2 The same or different; r 3 Is an olefin side chain with 15-17 carbons and 1-2 double bonds.
In some specific embodiments, the phloroglucinol derivatives are mainly 12 phloroglucinol derivatives isolated from black ink seeds of Eugenia jambolana Lam, and have the following specific chemical structural formula:
the phloroglucinol derivatives and the preparation method thereof are disclosed in Chinese patent CN 106916133B (application number: 201710034516.1; patent name: phloroglucinol derivatives with PTP1B inhibition activity, and the preparation method and application thereof), and the whole of the phloroglucinol derivatives is incorporated into the specification by reference. Briefly, the preparation method of the phloroglucinol derivative comprises the following steps:
1) Preparing extract
Pulverizing black graphite seed, cold soaking pulverized seed powder with petroleum ether at solid-to-liquid ratio of 1. And (3) after the filtrate is discarded, cold-soaking the filter residue for 3-4 times by using 70% acetone-water solution according to the solid-to-liquid ratio of 1. Concentrating the filtrate under reduced pressure to remove acetone and water to obtain crude extract.
2) Separating and purifying
(1) Dispersing the crude extract in water to obtain suspension, extracting the suspension with ethyl acetate, and concentrating the obtained extractive solution under reduced pressure to obtain ethyl acetate extract.
(2) Performing MCI small-pore resin column chromatography on the ethyl acetate extract, and performing gradient elution with methanol/water to obtain 100% water elution component, 60% methanol elution component, 80% methanol elution component and 100% methanol elution component respectively.
(3) The 100% methanol eluted fractions were subjected to silica gel column chromatography, petroleum ether-acetone gradient elution (15. And (3) carrying out Sephadex LH-20 gel column chromatography on the component II, eluting by 100% methanol, carrying out TLC (thin layer chromatography) color development, and combining similar components to obtain 6 sub-components (Fr.II1-II 6). Wherein the II5 fraction was purified by silica gel column chromatography, dichloromethane-ethyl acetate (60). II6 fraction was purified by semi-preparative high performance liquid chromatography (methanol-water 92. Subjecting the fraction III to Sephadex LH-20 gel column chromatography, eluting with 100% methanol, developing by TLC, and mixing similar fractions to obtain 4 sub-fractions (Fr.III1-III 4). Wherein the III2 fraction was subjected to silica gel column chromatography, dichloromethane-ethyl acetate (40.
In the preparation method, in the step of preparing the extract, petroleum ether is used for degreasing, and then 70% acetone-water is used for cold soaking.
In the above preparation method, in the separation and purification step, the ethyl acetate extract was separated using MCI small pore resin, and eluted with a methanol-water gradient (gradient of 0, 80, 20 and 100.
In the preparation method, in the separation and purification step, the semi-preparative high performance liquid chromatography column packing is RP-C 18 。
In a second aspect, the present invention provides a pharmaceutical composition comprising a phloroglucinol derivative as described above, and any combination thereof, together with a pharmaceutically acceptable excipient, diluent or carrier.
In a third aspect, the present invention provides a method of therapeutic or prophylactic treatment of cancer, comprising the steps of: providing a therapeutically or prophylactically effective amount of the phloroglucinol derivatives described above, and any combination thereof, or the pharmaceutical compositions described above, to a subject.
The subject is suspected of having, has, or is susceptible to a cancer selected from brain, lung, liver, stomach, oral cavity, head and neck, intestinal or rectal, colon, kidney, esophageal adenocarcinoma, esophageal squamous cell carcinoma, thyroid, bone, skin, non-small cell lung, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital tract cancer, testicular cancer, gastrointestinal stromal tumor, or prostate tumor.
The invention carries out in vitro and in vivo anti-tumor activity experiments on the acyl phloroglucinol derivative with the fat side chain, and the results show that the phloroglucinol derivative has obvious inhibitory activity on the growth of various tumor cells such as human breast cancer cell MDA-MB-231, human breast cancer cell MCF-7, liver cancer cell HepG2, neuroblastoma cell SH-SY5Y, bladder cancer cell UM-UC-3, non-small cell lung cancer cell A549, gastric cancer cell BGC-823, colon cancer cell HCT-116, cervical cancer cell Hela and the like. Therefore, can be used for preparing medicines for preventing and treating breast cancer, liver cancer, lung cancer, gastric cancer, colon cancer, cervical cancer, brain tumor and bladder cancer.
Drawings
Fig. 1A to 1C: compound 6 (jamunone M) has anti-tumor activity in tumor-bearing mice. FIG. 1A: detecting the tumor volume; FIG. 1B: mean tumor weight and growth inhibition rate; FIG. 1C: body weight of the mice.
Detailed Description
1. Term(s) for
In order that the present application may be more readily understood, certain technical and scientific terms are specifically defined below. Unless clearly defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
The term "inhibit growth" (e.g., in reference to a cell) is intended to include any measurable reduction in cell growth.
"administration," "administering," and "treating," when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "administration," "administering," and "treating" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. The treatment of the cells includes contacting the reagent with the cells and contacting the reagent with a fluid, wherein the fluid contacts the cells. "administering," "administering," and "treating" also mean treating, e.g., a cell, in vitro and ex vivo by an agent, diagnostic agent, binding composition, or by another cell. "treatment" when applied to a human, veterinary or research subject refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.
By "treating" is meant administering a therapeutic agent, such as comprising any of the phloroglucinol derivatives of the present application, either internally or externally to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in the subject patient or population in an amount effective to alleviate one or more symptoms of the disease, whether by inducing regression of such symptoms or inhibiting the development of such symptoms to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any particular disease symptom (also referred to as a "therapeutically effective amount") can vary depending on a variety of factors, such as the disease state, age, and weight of the patient, and the ability of the drug to produce a desired therapeutic effect in the patient. Whether a disease symptom has been reduced can be assessed by any clinical test commonly used by physicians or other health professional to assess the severity or progression of the symptom. Although embodiments of the present application (e.g., methods of treatment or articles of manufacture) may be ineffective in alleviating the symptoms of the disease of interest in a subset of patients, they should alleviate the symptoms of the disease of interest in a statistically significant number of patients as determined by any statistical test known in the art, such as the student test, chi-square test, U-test by Mann and Whitney, kruskal-Wallis test (H test), jonckheere-Terpstra test, and Wilcoxon test.
An "effective amount" comprises an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the method and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
As used herein, the expressions "cell," "cell line," and "cell culture" are used interchangeably, and all such designations include progeny thereof.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not.
By "pharmaceutical composition" is meant a composition containing one or more of the phloroglucinol derivatives described herein, together with other ingredients such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
2. Examples and test examples
The invention is further illustrated by the following examples, but not by way of limitation, in connection with the accompanying drawings. The following provides specific materials and sources thereof used in embodiments of the invention. However, it should be understood that these are merely exemplary and are not intended to limit the present invention, and that materials identical or similar in type, quality, nature, or function to the following reagents and instruments may be used in the practice of the present invention. The experimental procedures used in the following examples are all conventional procedures unless otherwise specified. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The embodiment is as follows: preparation of acylphloroglucinol derivatives having fatty side chains
1. Preparing extract of black ink seed
(1) Preparing the extract
The method comprises pulverizing black-bone rice seed (5 kg), cold soaking pulverized seed powder with 10L petroleum ether for 24 hr, filtering, and repeating the steps for 2 times. Discarding petroleum ether extract, cold soaking residue with 70% acetone-water solution 10L for 4 times, each for 24 hr, filtering, and mixing filtrates to obtain black ink seed extract.
(2) Preparing extract
Concentrating the above extractive solution at temperature of 40 deg.C or below under reduced pressure to remove acetone and water to obtain 1200g crude extract.
2. Separating and purifying
(1) Dispersing the above crude extract in 2.5L water to obtain suspension, extracting the suspension with ethyl acetate (2.5L) for 4 times, and concentrating the obtained extractive solution under reduced pressure to obtain ethyl acetate extract (185 g).
(2) Performing MCI small-pore resin column chromatography on the ethyl acetate extract, and performing gradient elution with methanol/water to obtain 100% water elution component, 60% methanol elution component, 80% methanol elution component and 100% methanol elution component respectively.
(3) The 100% methanol-eluted fraction (33 g) was subjected to silica gel column chromatography, petroleum ether-acetone gradient elution (15.
(4) Fraction II (2.2 g) was subjected to Sephadex LH-20 gel column chromatography, eluted with 100% methanol, and subjected to TLC to color-develop and combine similar fractions to give 6 subfractions (Fr.II1-II 6).
(5) II5 fraction (92.6 mg) was subjected to silica gel column chromatography, dichloromethane-ethyl acetate (60) elution, and further to semipreparative high performance liquid chromatography (methanol-water 93 7) to obtain compound 6 of the present invention (6.0 mg) and 10 (13.4 mg.
(6) II6 fraction (12.2 mg) was purified by semi-preparative high performance liquid chromatography (methanol-water 92.
(7) Fraction III (2.1 g) was subjected to Sephadex LH-20 gel column chromatography, eluted with 100% methanol, and subjected to TLC to develop color and combine similar fractions to give 4 subfractions (Fr.III1-III 4).
(8) The III2 fraction (260.0 mg) was subjected to silica gel column chromatography, dichloromethane-ethyl acetate (40.
3. Structural identification
According to UV, MS, IR and 1 H, 13 c NMR and other data confirm the structures of the compounds 1 to 12. The specific physical and chemical data are as follows:
compound 1: a light yellow gum; UV (ultraviolet) light max (MeOH)λ max (logε)345(4.11)，296(4.49)nm；ESIMS m/z405.2[M-H] - ； 1 H NMR(600MHz,DMSO-d6)δ(ppm):12.03(1H,s),5.81(1H,brs),5.80(1H,brs),3.02(1H,d,16.6Hz),2.55(1H,d,16.6Hz),1.81(2H,m),1.38(2H,m),1.20-1.30(24H,m),0.85(3H,t,6.6Hz)； 13 C NMR (150MHz, DMSO-d 6) delta (ppm) 196.3,167.2,163.5,160.9,103.2,101.8,96.1,95.8,45.4,40.6,31.8,29.6,29.5 (6 XC), 29.4 (2 XC), 29.2,23.6,22.6,14.4. The physicochemical properties and the spectral data of the compound 1 are consistent with those of spiralisone C, and the structure of the compound is identified as spiralisone C.
Compound 2: a light yellow gum; UV (ultraviolet) light max (MeOH)λ max (logε)346(4.23)，294(4.69)nm；IR(film)ν max 3384，2922，2852，1635，1611，1466，1366，1325，1295，1189，1123，896cm -1 ；HRESIMSm/z433.2955[M-H] - (calcd for C 26 H 41 O 5 ，433.2594)； 1 H NMR(600MHz,CDCl 3 )δ(ppm):12.20(1H,s),2.90(1H,d,17.0Hz),2.77(1H,d,17.0Hz),2.06(3H,s),2.04(3H,s),1.92(2H,m),1.54(2H,m),1.23-1.41(24H,m),0.88(3H,t,6.8Hz)； 13 C NMR(150MHz,CDCl 3 ) δ (ppm): 195.4,160.8,159.0,154.3,102.9,102.5,102.2,101.8,45.2,41.0,31.9,29.7 (5 XC), 29.6,29.5 (3 XC), 29.4,23.1,22.7,14.1,7.6,6.8. The physicochemical properties and the spectral data of the compound 2 are consistent with those of the structure of the protein I, and the structure of the protein I is identified to be the protein I.
Compound 3/4 white amorphous powder; UV (ultraviolet) light max (MeOH)λ max (logε)334(3.93)，293(4.58)nm；IR(film)ν max 3344，2921，2852，1639，1607，1465，1328，1161，1107，891，819cm -1 ；HRESIMSm/z 419.2822[M-H] - (calcd for C 25 H 39 O 5 419.2797); according to 1 H NMR spectrum analysis shows that the compound 3 and the compound 4 are a pair of isomers, and the mixing ratio is about 10. Compound 3: 1 H NMR(600MHz,DMSO-d6)δ(ppm):12.30(1H,s),5.89(1H,s),2.99(1H,d,16.8Hz),2.53(1H,d,16.8Hz),1.86(3H,s),1.81(2H,m),1.39(2H,m),1.22-1.32(24H,m),0.85(3H,t 6.6Hz)； 13 C NMR(150MHz,DMSO-d6)δ(ppm):196.2,165.4,160.8,158.3,103.1,102.6,101.5,95.4,45.6,40.6,31.7,29.6,29.5 (5 XC), 29.4 (3 XC), 29.2,23.6,22.6,14.4,7.4. Compound 4: 1 H NMR(600MHz,DMSO-d6)δ(ppm):11.98(1H,s),5.91(1H,s),2.99(1H,d,16.8Hz),2.53(1H,d,16.8Hz),1.87(3H,s),1.81(2H,m),1.44(2H,m),1.22-1.32(24H,m),0.85(3H,t 6.6Hz)； 13 c NMR (150MHz, DMSO-d 6) delta (ppm) 196.6,165.2,160.9,157.7,103.5,102.9,101.7,95.2,45.5,40.6,31.7,29.6,29.5 (5 XC), 29.4 (3 XC), 29.2,23.4,22.6,14.4,8.1. The physicochemical properties and the spectral data of the compound 3 and the compound 4 are consistent with those of the janone J and the janone K, and the structures of the janone J and the janone K are identified.
Compound 5: a colorless gum; UV (ultraviolet) light max (MeOH)λ max (logε)332(4.06)，290(4.52)nm；IR(film)ν max 3320，2926，2855，1642，1508，1464，1330，1161，1068，1011，885，837cm -1 ；HRESIMSm/z 403.2497[M-H] - (calcd for C 24 H 35 O 5 ，403.2484)；ESI-MS/MS[M+H-H 2 O] + m/z 387.0； 1 H NMR(600MHz,CDCl 3 )δ(ppm):11.95(1H,s),5.99(1H,brs),5.93(1H,brs),5.37(2H,m),2.91(1H,d,16.7Hz),2.77(1H,d,16.7Hz),2.03(2H,m),1.90(2H,m),1.51(2H,m),1.27-1.40(18H,m),0.88(3H,t,6.8Hz)； 13 C NMR(150MHz,CDCl 3 ) Delta (ppm) 194.9,164.5,163.8,160.0,130.0,129.6,102.5,102.3,96.6,96.0,44.8,41.1,31.7,29.7,29.6,29.4,29.3,29.1,28.9,27.2,27.1,23.1,22.6,14.0. The physicochemical properties and the spectral data of the compound 5 are consistent with those of the structure of the protein L, and the structure of the compound is identified as the protein L.
Compound 6: a light yellow gum; UV (ultraviolet) light max (MeOH)λ max (logε)330(3.88)，290(4.41)nm；IR(film)ν max 3360，2924，2854，1641，1464，1328，1278，1161，1067，886，834cm -1 ；HRESIMSm/z 431.2794[M-H] - (calcd for C 26 H 39 O 5 ，431.2797)；ESI-MS/MS[M+H-H2O] + m/z 415.0； 1 H NMR(600MHz,CDCl 3 )δ(ppm):12.20(1H,s),5.36(2H,m),2.90(1H,d,16.9Hz),2.77(1H,d,16.9Hz),2.07(3H,s),2.05(3H,s),2.03(2H,m),1.92(2H,m),1.55(2H,m),1.27-1.40(18H,m),0.89(3H,t,6.8Hz). 13 C NMR(150MHz,CDCl 3 ) δ (ppm) 195.3,160.7,158.9,154.2,130.0,129.6,102.9,102.4,102.1,101.7,45.1,40.9,31.7,29.7,29.6,29.4,29.3,29.1,28.9,27.2,27.1,22.9,22.6,14.0,7.5,6.7. The physicochemical properties and the spectral data of the compound 6 are consistent with those of the structure of janone M, and the structure of the compound is identified as the janone M.
Compound 7/8: white amorphous powder; UV light max (MeOH)λ max (logε)338(3.73)，292(4.28)nm；IR(film)ν max 3353，2925，2854，1638，1607，1461，1328，1160，1109，889，820cm -1 ；HRESIMSm/z 419.2808[M+H] + (calcd for C 25 H 39 O 5 ，419.2797)；ESI-MS/MS[M+H-H2O] + m/z 401.0; based on it 1 H NMR spectrum data show that the compound 7 and the compound 8 are a pair of isomers, and the mixing ratio is about 10. Compound 7: 1 H NMR(600MHz,DMSO-d6)δ(ppm):12.29(1H,s),5.91(1H,s),5.33(2H,m),2.99(1H,d,16.8Hz),2.55(1H,d,16.8Hz),1.99(2H,m),1.86(3H,s),1.82(2H,m),1.38(2H,m),1.24-1.33(18H,m),0.85(3H,t,6.8Hz)； 13 c NMR (150MHz, DMSO-d 6) delta (ppm) 196.3,164.9,160.8,158.3,130.1 (2 XC), 103.1,102.6,101.6,95.4,45.6,40.6,31.6,29.6 (2 XC), 29.5,29.3,29.0,28.8,27.1 (2 XC), 23.6,22.6,14.4,7.4. Compound 8: 1 H NMR(600MHz,DMSO-d6)δ(ppm):11.97(1H,s),5.93(1H,s),5.33(2H,m),2.99(1H,d,16.8Hz),2.53(1H,d,16.8Hz),1.99(2H,m),1.87(3H,s),1.82(2H,m),1.44(2H,m),1.24-1.33(18H,m),0.85(3H,t,6.8Hz)； 13 c NMR (150MHz, DMSO-d 6) delta (ppm) 196.7,165.1,160.9,157.7,130.1 (2 XC), 103.5,102.9,101.8,95.1,45.5,40.6,31.6,29.6 (2 XC), 29.5,29.2,29.0,28.8,27.1 (2 XC), 23.4,22.6,14.4,8.1. The physicochemical properties and the spectral data of the compound 7 and the compound 8 are consistent with those of the janone N and janone O, and the structures of the janone N and janone O are identified.
Compound 9: a colorless gum; UV (ultraviolet) light max (MeOH)λ max (logε)328(3.90)，287(4.42)nm；IR(film)ν max 3334，3010，2926，2855，1641，1609，1464，1328，1276，1161，1066，1011，885，835，722cm -1 ；HRESIMSm/z 429.2642[M-H] - (calcd for C 26 H 37 O 5 ，429.2641)； 1 H NMR(600MHz,CDCl 3 )δ(ppm):11.95(1H,s),5.99(1H,brs),5.93(1H,brs),5.30-5.42(4H,m),2.91(1H,d,16.9Hz),2.79(2H,m),2.77(1H,d,16.9Hz),2.08(2H,m),2.06(2H,m),1.90(2H,m),1.51(2H,m),1.31-1.41(14H,m),0.90(3H,t,6.8Hz)； 13 C NMR(150MHz,CDCl 3 ) Delta. (ppm) 194.9,164.5,163.8,160.0,130.2,129.9,128.0,127.8,102.5,102.3,96.6,96.0,44.8,41.1,31.5,29.5,29.4,29.3 (2 XC), 29.1,27.1 (2 XC), 25.6,23.1,22.5,14.0. The physicochemical properties and the spectral data of the compound 9 were consistent with those of janone E, and the structure thereof was identified as janone E.
Compound 10: a light yellow gum; UV light max (MeOH)λ max (logε)350(3.99)，296(4.51)nm；IR(film)ν max 3389，2929，2857，1711，1635，1613，1461，1364，1239，1190，1122，937，811cm -1 ；HRESIMS m/z457.2950[M-H] - (calcd for C 28 H 41 O 5 ，457.2959)； 1 H NMR(600MHz,CDCl 3 )δ(ppm):12.20(1H,s),5.30-5.42(4H,m),2.89(1H,d,16.9Hz),2.79(2H,m),2.76(1H,d,16.9Hz),2.08(4H,m),2.07(3H,s),2.05(3H,s),1.93(2H,m),1.54(2H,m),1.31-1.42(14H,m),0.90,t(3H,t,6.9Hz)； 13 C NMR(150MHz,CDCl 3 ) δ (ppm) 195.3,160.6,158.9,154.2,130.2,129.9,128.0,127.8,102.8,102.4,102.1,101.7,45.1,40.9,31.5,29.5,29.4,29.3 (2 XC), 29.1,27.1 (2 XC), 25.6,22.9,22.5,14.0,7.5,6.7. The physicochemical properties and the spectral data of compound 10 were consistent with those of janone F, and the structure was identified as janone F.
Compound 11/12 is a white gum; UV light max (MeOH)λ max (logε)344(3.94)，293(4.51)nm；IR(film)ν max 3313，3010，2927，2856，1639，1609，1498，1462，1329，1188，1161，1109，893cm -1 ；HRESIMS m/z467.2756[M+Na] + (calcd for C 27 H 40 O 5 Na, 467.2768); according to 1 H NMR spectrum analysis shows that the compound 11 and the compound 12 are a pair of isomers, and the mixing ratio is about 10. Compound 11: 1 H NMR(600MHz,CDCl 3 )δ(ppm):12.21(1H,s),5.91(1H,s),5.30-5.42(4H,m),2.88(1H,d,16.3Hz),2.78(2H,m),2.75(1H,d,16.3Hz),2.06(4H,m),2.03(3H,s),1.88(2H,m),1.52(2H,m),1.30-1.42(14H,m),0.89(3H,t,6.8Hz)； 13 C NMR(150MHz,CDCl 3 ) δ (ppm) 195.0,162.2,161.4,157.4,130.3,130.0,128.1,127.9,103.9,102.4,102.1,95.3,44.8,41.1,31.5,29.6,29.5,29.4 (2 XC), 29.2,27.2 (2 XC), 25.7,23.2,22.6,14.1,6.6. Compound 12: 1 H NMR(600MHz,CDCl 3 )δ(ppm):11.89(1H,s),5.99(1H,s),5.30-5.42(4H,m),2.88(1H,d,16.3Hz),2.78(2H,m),2.75(1H,d,16.3Hz),2.06(4H,m),2.01(3H,s),1.93(2H,m),1.52(2H,m),1.30-1.42(14H,m),0.89(3H,t,6.8Hz)； 13 C NMR(150MHz,CDCl 3 ) Delta (ppm): 195.4,162.6,161.4,156.8,130.3,130.0,128.1,127.9,103.5,102.6,101.9,96.1,44.7,41.0,31.5,29.6,29.5,29.4, (2 XC), 29.2,27.2 (2 XC), 25.7,23,22.6,14.1,7.4. The physicochemical properties and the spectral data of the compound 11 and the compound 12 are consistent with those of the janone G and the janone H, and the structures of the janone G and the janone H are identified.
Test example 1: cytotoxic Activity assay
1 Experimental method
In the test examples, the cell lines used were all cultured in complete medium (DMEM medium containing 10% fetal bovine serum, 1% L-glutamine, 100U/mL penicillin, 100. Mu.g/mL streptomycin) and placed at 5% CO 2 And incubating in a constant temperature incubator at 37 ℃. The antiproliferative activity screening was performed as follows:
(1) Collecting cancer cell lines (MDA-MB-231, MCF-7, hepG2, SH-SY5Y, UM-UC-3, A549, BGC-823, HCT-116 or Hela) at logarithmic phase, adjusting the concentration of the cell suspension to 3-5 × 10 3 Cell density of cells/well was seeded in 96-well plates and 100. Mu.L of cell suspension was added per well.
(2) After the cells are placed in a cell culture box for culture, drugs (the compounds 1-12 prepared in the above embodiment) are added according to concentration gradient in sequence after the cells are attached to the walls, so that the final concentration of the compounds is 0.41, 1.23, 3.7, 11.1, 33.3 and 100 mu M, 3 compound wells are arranged at each concentration, and the addition of DMSO with the same volume is used as a blank control and adriamycin (DOX) is used as a positive control drug.
(3)5％CO 2 Incubation at 37 ℃ for 48h, followed by addition of 20. Mu.L of 0.5% MTT solution and further incubation for 4h; the culture medium was aspirated and the culture was terminated.
(4) Adding 150 μ L/hole DMSO, shaking for 5-10min, dissolving crystal, detecting OD value at 570nm wavelength with enzyme labeling instrument, calculating cell proliferation inhibition rate according to the following formula, and analyzing and calculating with SPSS software to obtain half Inhibition Concentration (IC) of the compound to corresponding cancer cells 50 )。
Cell proliferation inhibition rate = [ OD ] 570 (blank control group) -OD 570 (drug group)]/OD 570 (blank control) x 100%.
2 results of the experiment
2.1 Compounds 1-12 prepared in the above example show varying degrees of inhibitory activity against both breast cancer cell lines MDA-MB-231 and MCF-7, half the inhibitory concentration IC 50 6.79 to 100 mu M. The results are shown in Table 1.
TABLE 1 growth inhibitory Activity of Compounds 1-12 on MDA-MB-231 and MCF-7
2.2 Compound 6 (janone M) shows growth inhibition activities of different degrees on 9 tumor cell lines MDA-MB-231, MCF-7, hepG2, SH-SY5Y, UM-UC-3, A549, BGC-823, HCT-116 and Hela, has obviously stronger effects on breast cancer cells MDA-MB-231 and MCF-7 than other tumor cell lines, wherein the inhibition activity on triple-negative breast cancer cell lines MDA-MB-231 is strongest, and IC is stronger than that on other tumor cell lines 50 The value was 6.79. + -. 0.05. Mu.M. The results are given in Table 2 below.
TABLE 2 inhibitory Activity of Compound 6 (janone M) and the Positive control Adriamycin (DOX) on various cells
3 conclusion of the experiment
The acyl phloroglucinol derivatives with the fat side chain have better tumor growth inhibition activity, and the compound 6 (janone M) has better growth inhibition activity on human breast cancer cells MDA-MB-231, human breast cancer cells MCF-7, liver cancer cells HepG2, neuroblastoma cells SH-SY5Y, bladder cancer cells UM-UC-3, non-small cell lung cancer cells A549, stomach cancer cells BGC-823, colon cancer HCT-116 and cervical cancer cells Hela; especially, the inhibitory activity on breast cancer cells is the most remarkable. Therefore, the phloroglucinol derivatives provided by the invention can be used for preparing medicines for treating or preventing cancers, in particular for treating breast cancers.
Test example 2: in vivo activity experiment of nude mice with subcutaneous transplantation tumor of human breast cancer cell strain
1 establishment and administration scheme of human breast cancer cell line subcutaneous transplantation tumor nude mouse model
(1) Feeding the nude mice: the animals used in this test example were female SPF BALB/c-nu mice. The nude mice are bred at the temperature of 25-28 ℃, have a good ventilation environment, and maintain the light and shade alternation of 12h light/12 h dark every day. Changing the sterile padding and the edible water every 2-3 days. Within 2 weeks of rearing, nude mice were closely observed for growth: the skin color brightness degree, whether the body weight is reduced or not, whether the drinking water and the eating are normal or not and whether the pathological manifestations exist or not.
(2) Preparing a cell suspension: selecting triple negative breast cancer MDA-MB-231 cells with log phase and excellent growth state, centrifuging at 1000rpm for 5min, re-suspending the cells with sterile PBS, counting under microscope, and adjusting cell concentration to 4 × 10 7 And (4) per mL, and placing on ice to keep the cell vitality.
(3) Inoculation: nude mice were fixed and local disinfection of the skin of nude mice was required before inoculation. The MDA-MB-231 cells were inoculated into the right back of nude mice near the underarm by subcutaneous injection using a disposable sterile syringe, the needle was slowly pulled out, and the pressure was applied with a medical cotton swab for about 30 s. The inoculation volume of each nude mouse is about 150. Mu.L, and the number of cells is about 6X 10 6 And (4) respectively.
(4) Neoplastic status and grouping: after the completion of the cancer cell inoculation, the growth state of the nude mice was observed at all times. After 2-3 days, tumor bulges of varying degrees were visible at the inoculation site of each nude mouse. Further observation is carried out for 5 days until the tumor volume is about 60mm 3 Or the long diameter of the tumor body isAbout 5-6 mm. The success of establishing the transplanted tumor model is shown. Nude mice were randomly divided into three groups: control group (5% DMSO and 95% physiological saline), compound 6 (jamone M) was administered to the low dose group (15 mg/kg) and Compound 6 (jamone M) was administered to the high dose group (30 mg/kg), with 5 of them each.
(5) Administration and index determination: the preparation is administered by intraperitoneal injection, once every other day for 3 weeks according to the dosage scheme in (4). The body weight of the nude mice was weighed before each administration, and the tumor size was measured with a vernier caliper. The volume of the tumor body is calculated according to the following formula.
V (tumor volume, mm) 3 ) = L (long diameter, mm). Times.W 2 (minor diameter, mm). Times.0.5
(6) Stripping tumor and taking materials: 24h after the last administration, the experiment was terminated and the mice were weighed. Subsequently, nude mice were sacrificed by cervical dislocation, and the tumor bodies were sequentially exfoliated and weighed.
2, experimental results:
the experimental result is shown in fig. 1A, compared with the tumor-bearing mice without administration, the treatment group of the janone M can significantly reduce the tumor growth rate in the tumor-bearing mice, and the tumor volume increases slowly and is dose-dependent. The inhibition rates of tumor growth in tumor-bearing mice by the treatment group of janone M after 3 weeks of administration were 53.6% (administration dose of 15 mg/kg) and 79.3% (administration dose of 30 mg/kg), respectively, showing that they have activity against breast cancer proliferation in vivo (FIG. 1B). There was no significant change in body weight of the three groups of mice, indicating that JM was not severely toxic to the mice (fig. 1C).
3. Conclusion of the experiment
The pharmacological experiment in vivo of the tumor-bearing mice shows that the phloroglucinol derivative with the alkyl side chain has better anticancer activity. Therefore, the phloroglucinol derivatives of the present invention can be used for preparing medicines for treating and preventing cancers.
The above description of exemplary embodiments has been presented only to illustrate the technical solution of the invention and is not intended to be exhaustive or to limit the invention to the precise form described. Obviously, many modifications and variations are possible in light of the above teaching to those skilled in the art. The exemplary embodiments were chosen and described in order to explain certain principles of the invention and its practical application to thereby enable others skilled in the art to understand, implement and utilize the invention in various exemplary embodiments and with various alternatives and modifications. It is intended that the scope of the invention be defined by the following claims and their equivalents.
Claims (1)
1. Use of a phloroglucinol derivative for the preparation of a medicament for the treatment and/or prevention of cancer, wherein the phloroglucinol derivative is:
wherein the cancer is triple negative breast cancer.
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