CN115677811A - Application of pachymic acid derivative and antitumor drug and preparation method thereof - Google Patents
Application of pachymic acid derivative and antitumor drug and preparation method thereof Download PDFInfo
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- HOMSOWZTBJWNHP-UHFFFAOYSA-N 5-chlorothiadiazole Chemical class ClC1=CN=NS1 HOMSOWZTBJWNHP-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 title abstract description 6
- 201000007270 liver cancer Diseases 0.000 claims abstract description 7
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 7
- 230000002159 abnormal effect Effects 0.000 claims abstract description 6
- 230000004663 cell proliferation Effects 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 3
- 230000004660 morphological change Effects 0.000 claims description 3
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical group C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 2
- 150000004820 halides Chemical group 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- VDYCLYGKCGVBHN-UHFFFAOYSA-N pachymaic acid Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC(=C)C(C)C)C(O)=O)C(O)CC21C VDYCLYGKCGVBHN-UHFFFAOYSA-N 0.000 abstract description 13
- SRDNLMOBFKJOSD-UHFFFAOYSA-N pachymic acid Natural products CC12CCC(OC(C)=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C(O)=O)C(O)CC21C SRDNLMOBFKJOSD-UHFFFAOYSA-N 0.000 abstract description 13
- 210000004027 cell Anatomy 0.000 abstract description 10
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 238000000338 in vitro Methods 0.000 abstract description 5
- 230000001028 anti-proliverative effect Effects 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 101100395824 Solanum lycopersicum HSC-2 gene Proteins 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XBZYWSMVVKYHQN-MYPRUECHSA-N (4as,6as,6br,8ar,9r,10s,12ar,12br,14bs)-10-hydroxy-2,2,6a,6b,9,12a-hexamethyl-9-[(sulfooxy)methyl]-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-4a-carboxylic acid Chemical compound C1C[C@H](O)[C@@](C)(COS(O)(=O)=O)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C XBZYWSMVVKYHQN-MYPRUECHSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 244000248825 Peltandra virginica Species 0.000 description 2
- 235000001188 Peltandra virginica Nutrition 0.000 description 2
- 235000008599 Poria cocos Nutrition 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 229960004630 chlorambucil Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001558929 Sclerotium <basidiomycota> Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- -1 antibacterial Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- ZQIOPEXWVBIZAV-ZKYCIREVSA-N lanostane Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@@H]2[C@]2(C)CC[C@H]([C@H](C)CCCC(C)C)[C@@]2(C)CC1 ZQIOPEXWVBIZAV-ZKYCIREVSA-N 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application discloses an application and a preparation method of a pachymic acid derivative and an anti-tumor drug in the field of medicinal chemistry, wherein the 3/16/21 modified pachymic acid derivative is provided on the basis of pachymic acid, is used for treating various diseases related to abnormal cell proliferation and the like, particularly is used for treating tumor diseases, and can have strong in-vitro anti-proliferation activity on human liver cancer cells and human oral squamous tumor cells.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to application of a pachymic acid derivative and an antitumor drug and a preparation method thereof.
Background
The sclerotium of the wood rotting fungus tuckahoe contains active ingredients such as beta-pachyman, triterpenoid pachymic acid, 3 beta-hydroxy lanostane trienoic acid and the like, and is widely applied to various traditional Chinese medicines and health-care foods in China. Pachymic Acid (PA) is one of the main active ingredients in tuckahoe, and is a natural lanostane triterpenoid. Research shows that pachymic acid has obvious pharmacological activity, such as antitumor, antiphlogistic, antibacterial, sedative and hypnotic. In anti-tumor terms, pachymic acid can inhibit the proliferation of a variety of tumor cells by down-regulating the expression of CDK1, CDK2, CDK4 and cyclinE, thereby blocking the cell cycle, including MDA-MB-231, SGC-7901 and MKN-49P cells (J Ethnopharmacol 2020,257 112851, oncocol let 2018,16 2512517, anticancer Drugs 2017, 28. Meanwhile, pachymic acid also induces apoptosis of various tumor cells, including cells such as EJ, SK-BR-3, PANC-1, MIA PaCa 2, DU145, etc. (phytotherm Res 2015,29 1516 biochem biophysis Res commu 2005,332, plos One 2015 10, ee0122270), the compound formula of pachymic acid is as follows:
therefore, the applicant provides 3/16/21 modified pachymic acid derivatives on the basis of pachymic acid, is used for treating various diseases related to abnormal cell proliferation and the like, particularly is used for treating tumor diseases, and can have strong in-vitro anti-proliferation activity on human liver cancer cells and human oral squamous tumor cells.
Disclosure of Invention
The invention aims to provide an application and a preparation method of a pachymic acid derivative and an anti-tumor drug, so as to provide a 3/16/21-modified pachymic acid derivative which can be used for treating various diseases related to abnormal cell proliferation and the like, in particular to a drug for treating tumor diseases.
In order to achieve the purpose, the invention provides the following technical scheme: the general formula of the pachymic acid derivative is shown as the following formulas (I), (II) and (III):
wherein, R represents: benzyl, substituted benzyl, heteroaromatic methyl, substituted heteroaromatic methyl, naphthylmethyl or substituted naphthylmethyl.
The preparation method of the compounds shown in the general formulas (I), (II) and (III) is as follows:
wherein R is as defined above, wherein a to c represent reaction conditions;
a: the reagent is a halide, and a solvent I and an alkaline catalyst are added during reaction at the reaction temperature of 20-35 ℃;
b: the reducing agent is sodium borohydride, a solvent II is added during the reaction, and the reaction temperature is 50-90 ℃;
c: the oxidant is a dess-martin reagent, the solvent III is added during the reaction, and the reaction temperature is 20-35 ℃.
Further, the solvent I: one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide and acetone; basic catalyst: triethylamine, piperidine, sodium acetate, potassium carbonate, sodium carbonate, pyridine, cesium carbonate, lithium hydroxide and morpholine.
Further, the solvent II: one of N, N-dimethylformamide, N-dimethylacetamide, ethanol, methanol, tert-butanol, dimethyl sulfoxide and acetone.
Further, the solvent III: one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, ethanol, methanol, dichloromethane, tert-butanol or acetone.
Furthermore, the solvent I is N, N-dimethylformamide, and the alkaline catalyst is potassium carbonate.
Further, the solvent II is ethanol.
Furthermore, dichloromethane is used as the solvent III.
An application of pachymic acid derivative in preparing medicine for preventing and treating diseases related to abnormal cell proliferation and morphological change is disclosed.
Furthermore, the application of the pachymic acid derivative in preparing the medicine for treating human liver cancer or human oral squamous cell carcinoma.
The working principle and the beneficial effects of the invention are as follows: pharmacological experiments of the prepared pachymic acid derivative show that the pachymic acid derivative has certain in-vitro antiproliferative activity on human liver cancer cells HepG2 and human oral squamous tumor cells HSC-2. Therefore, the pachymic acid derivative can be used for preventing and treating various diseases related to abnormal cell proliferation, morphological change and the like, in particular to a medicament for treating or preventing human liver cancer or human oral squamous cell carcinoma.
Detailed Description
The following is further detailed by way of specific embodiments:
the mass spectrometer is Waters Xevo G2-S QTOF model, the nuclear magnetic resonance apparatus is Agilent DD2400-MR-400 model, the thin layer chromatography plate and the silica gel are purchased from Qingdao oceanic chemical plant, the pachymic acid is purchased from Dou Pufei Ded biotechnology Limited company, and other used reagents are analytical purifiers.
Example 1: preparation of Compound I
Funaric acid (0.09 mmol) was added to anhydrous N, N-dimethylformamide (2 mL), and benzyl bromide (0.18 mmol) and potassium carbonate (0.18 mmol) were added. The reaction solution was stirred at room temperature for 2 hours. Quenching the reaction by ammonium chloride solution, extracting with dichloromethane for three times, combining organic layers, washing with saturated salt water, drying over night by anhydrous sodium sulfate, and filtering to obtain a crude product. Purification by column chromatography gave a white solid (compound I) in 78% yield.
The characterization data are: 1H (400mhz, cdcl3): δ 7.38-7.29 (m, 5H), 5.16 (d, J =12.2hz, 1h), 5.05 (d, J =12.2hz, 1h), 4.71 (s, 1H), 4.63 (s, 1H), 4.48 (dd, J =4.1,11.5hz, 1h), 4.11-4.06 (m, 1H), 2.48 (dt, J =2.7,11.0hz, 1h), 2.18-2.10 (m, 3H), 2.03 (s, 3H), 1.99-1.77 (m, 9H), 1.69-1.46 (m, 6H), 1.31-1.24 (m, 2H), 1.14-1.06 (m, 5H), 0.95-0.91 (m, 9H), 0.86 (s, 69H), 0.86 (s, 6H), 0.3H), 0.95-0.91 (m, 9H); 13C (100MHz, CDCl3): delta 175.60,171.07,155.04,135.75,134.24,134.06,128.59,128.49,128.21,106.75,80.78,77.05,65.98,56.85,50.37,48.04,47.07,45.88,42.71,37.76,36.83,35.10,33.64,32.11,30.66,28.85,27.87,26.36,25.14,24.07,21.81,21.70,21.34,20.39,19.10,17.97,17.39,16.52; HRMS (ESI) calculated for C40H58O5Na [ M + Na ] +641.4176, found 641.4173.
Example 2: preparation of Compound II
Compound I (0.08 mmol) and sodium borohydride (0.8 mmol) were dissolved in anhydrous ethanol (3 mL). The reaction solution was heated to 80 ℃ under argon for 4 hours, and then concentrated. Purification by column chromatography gave a white solid (compound ii) in 58% yield.
The characterization data are: 1H (400mhz, cdcl3): δ 7.39-7.31 (m, 5H), 5.16 (d, J =12.2hz, 1h), 5.07 (d, J =12.2hz, 1h), 4.72 (s, 1H), 4.63 (s, 1H), 4.16-4.07 (m, 2H), 3.22 (dd, J =4.0 11.4hz, 1h), 2.51-2.45 (m, 1H), 2.20-2.10 (m, 3H), 2.04-1.79 (m, 9H), 1.69-1.64 (m, 3H), 1.61-1.54 (m, 2H), 1.52-1.41 (m, 2H), 1.30-1.22 (m, 3H), 1.09 (s, 3H), 0.99 (m, 3H), 0.92-0.96 (m, 0.79H), 0.9H, 3H), 0.79 (m, 3H); 13C (100MHz, CDCl3): delta 175.65,155.06,135.72,134.41,133.95,128.61,128.52,128.25,106.77,78.84,77.16,66.03,56.96,50.24,48.04,46.97,45.92,42.69,38.85,36.95,35.42,33.64,32.10,30.74,28.87,27.94,27.71,26.45,25.14,21.81,21.69,20.39,19.07,18.09,17.41,15.43; HRMS (ESI) calculated for C38H56O4Na [ M + Na ] +599.4070, found 599.4069.
Example 3: preparation of Compound III
Compound I (0.08 mmol) was added to dry dichloromethane (3 mL). Then Daiss-Martin reagent (0.15 mmol) was added. The reaction was stirred at room temperature for 3 hours under argon. The reaction was quenched with saturated sodium sulfite solution and extracted three times with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate overnight, and filtered to give a crude product. Purification by column chromatography gave a white solid (compound III 0) in 100% yield.
The characterization data are: 1H (400mhz, cdcl3): δ 7.38-7.31 (m, 5H), 5.20 (d, J =12.1hz, 1h), 5.04 (d, J =12.1hz, 1h), 4.71 (s, 1H), 4.65 (s, 1H), 4.49 (dd, J =4.1,11.6hz, 1h), 2.69-2.62 (m, 1H), 2.58-2.51 (m, 2H), 2.30 (d, J =18.2hz, 1h), 2.20-2.14 (m, 1H), 2.05 (s, 3H), 1.96-1.87 (m, 4H), 1.84-1.75 (m, 2H), 1.72-1.51 (m, 6H), 1.36-1.21 (m, 4H), 1.16-1.12 (m, 2H), 0.9H), 0.93 (s, 0.9H); 13C (100MHz, CDCl3): delta 217.91,174.41,171.03,154.84,135.72,135.46,131.43,128.75,128.55,128.36,106.85,80.60,66.21,57.28,50.26,46.34,44.09,43.91,43.26,37.75,37.00,34.93,33.52,31.93,29.74,28.46,27.87,26.75,24.93,24.00,21.81,21.72,21.36,20.04,19.11,17.91,16.88,16.52; HRMS (ESI) calculated for C40H56O5Na [ M + Na ] +639.4019, found 639.4015.
Pharmacological activity test method and results:
CCK-8 method for testing in vitro antitumor activity
Positive drugs: pachymic Acid (PA) and Chlorambucil (CHL)
The experimental method comprises the following steps:
HepG2 and HSC-2 cells in logarithmic growth phase are respectively added into a 96-well plate, and after 24-well plates are cultured under the conditions of 5% CO2 and 37 ℃, test compounds with different concentrations are added, and a negative and positive control group is established. The incubation was carried out for 72 hours, CCK-8 reagent (10. Mu.L) was added, and the incubation was continued for 2 hours. Finally, the OD value of each well is read by a microplate reader, and the half inhibitory concentration (IC 50) value is calculated.
The results of the antitumor activity of part of the compounds in vitro are as follows:
TABLE 1 in vitro antiproliferative Activity of partial compounds of the invention on HepG2 and HSC-2 cells
The results show that the compound has inhibitory activity to two tumor cell strains of HepG2 and HSC-2 to different degrees. Overall, the inhibitory activity of the compound on HSC-2 oral cancer cells is stronger than that of HepG2 liver cancer cells. Among them, compound II has the strongest activity, and has IC50 values of 22.15 +/-1.18 and 18.83 +/-8.89 mu M on HepG2 and HSC-2 cells respectively, which are stronger than the parent compound pachymic acid and the positive drug chlorambucil.
It will be apparent to those skilled in the art that various changes and modifications can be made without departing from the structure of the invention, and it is intended to cover all modifications and equivalents of the invention without departing from the spirit and scope of the invention. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (10)
1. Pachymic acid derivatives characterized by the general formula of the compounds as shown in formulas (I), (II), (III):
wherein, R represents: benzyl, substituted benzyl, heteroaromatic methyl, substituted heteroaromatic methyl, naphthylmethyl or substituted naphthylmethyl.
2. The method for preparing pachymic acid derivatives according to claim 1, wherein the compounds represented by the general formulae (I), (II), (III) are prepared as follows:
wherein R is as defined above, wherein a to c represent reaction conditions;
a: the reagent is a halide, and a solvent I and an alkaline catalyst are added during the reaction, wherein the reaction temperature is 20-35 ℃;
b: the reducing agent is sodium borohydride, a solvent II is added during the reaction, and the reaction temperature is 50-90 ℃;
c: the oxidant is a dess-martin reagent, the solvent III is added during the reaction, and the reaction temperature is 20-35 ℃.
3. The method for preparing pachymic acid derivatives according to claim 2, wherein the ratio of the solvent I: one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, dimethyl sulfoxide and acetone; basic catalyst: triethylamine, piperidine, sodium acetate, potassium carbonate, sodium carbonate, pyridine, cesium carbonate, lithium hydroxide and morpholine.
4. The method for preparing pachymic acid derivatives according to claim 3, wherein the ratio of the solvent II: one of N, N-dimethylformamide, N-dimethylacetamide, ethanol, methanol, tert-butanol, dimethyl sulfoxide and acetone.
5. The method for preparing pachymic acid derivatives according to claim 4, wherein the ratio of the solvent III: one of N, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran, ethanol, methanol, dichloromethane, tert-butanol or acetone.
6. The method for preparing pachymic acid derivatives according to claim 3, wherein the solvent I is N, N-dimethylformamide and the basic catalyst is potassium carbonate.
7. The method for preparing pachymic acid derivative according to claim 4, wherein the solvent II is ethanol.
8. The method for preparing pachymic acid derivative according to claim 5, wherein said solvent III is dichloromethane.
9. The use of the pachymic acid derivative according to any one of claims 1 to 8 for the preparation of a medicament for the prevention and treatment of various diseases associated with abnormal cell proliferation and morphological changes.
10. Use of a pachymic acid derivative according to claim 9 for the preparation of a medicament for the treatment of human liver cancer or human oral squamous cell carcinoma.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3127423A (en) * | 1962-09-21 | 1964-03-31 | Olin Mathieson | Phenyl derivatives of methylsterols and process for production thereof |
| US3369032A (en) * | 1966-10-31 | 1968-02-13 | Squibb & Sons Inc | Methyl-3beta-acetoxy-16-ketoburico-8, 24(28)-dien-21-oate |
| CN102675401A (en) * | 2011-03-09 | 2012-09-19 | 雷海民 | Preparation of anti-tumor medicine LQC-Y and application thereof |
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- 2022-11-09 CN CN202211398853.6A patent/CN115677811A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3127423A (en) * | 1962-09-21 | 1964-03-31 | Olin Mathieson | Phenyl derivatives of methylsterols and process for production thereof |
| US3369032A (en) * | 1966-10-31 | 1968-02-13 | Squibb & Sons Inc | Methyl-3beta-acetoxy-16-ketoburico-8, 24(28)-dien-21-oate |
| CN102675401A (en) * | 2011-03-09 | 2012-09-19 | 雷海民 | Preparation of anti-tumor medicine LQC-Y and application thereof |
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| Title |
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| HEZHEN WANG等: "Synthesis and bioactivity evaluation of pachymic acid derivatives as potential cytotoxic agents", 《MEDICINAL CHEMISTRY RESEARCH 》, vol. 32, pages 342, XP037938047, DOI: 10.1007/s00044-022-03009-3 * |
| TAKAAKI TAI等: "Isolation of lanostane-type triterpene acids having an acetoxyl group from sclerotia of Poria cocos", 《PHYTOCHEMISTRY》, vol. 40, no. 1, pages 225 - 231, XP002666236, DOI: 10.1016/0031-9422(95)00182-7 * |
| 沈芊等: "茯苓三萜成分及其衍生物的构效关系研究", 《中国药物化学杂志》, vol. 9, no. 4, pages 271 - 276 * |
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