CN110981886A - Hydrogen sulfide donor derivative of diterpene dimer and preparation method and application thereof - Google Patents
Hydrogen sulfide donor derivative of diterpene dimer and preparation method and application thereof Download PDFInfo
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- CN110981886A CN110981886A CN201911279063.4A CN201911279063A CN110981886A CN 110981886 A CN110981886 A CN 110981886A CN 201911279063 A CN201911279063 A CN 201911279063A CN 110981886 A CN110981886 A CN 110981886A
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- hydrogen sulfide
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- diterpene
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- 239000000539 dimer Substances 0.000 title claims abstract description 19
- 229930004069 diterpene Natural products 0.000 title claims abstract description 19
- 229910000037 hydrogen sulfide Inorganic materials 0.000 title claims abstract description 18
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 150000004141 diterpene derivatives Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- IWBBKLMHAILHAR-UHFFFAOYSA-N chembl402341 Chemical compound C1=CC(O)=CC=C1C1=CC(=S)SS1 IWBBKLMHAILHAR-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 201000007270 liver cancer Diseases 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- JMSRBKPMLUGHCR-UHFFFAOYSA-N bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- 230000032050 esterification Effects 0.000 claims 1
- 150000002391 heterocyclic compounds Chemical class 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 4
- 210000004027 cell Anatomy 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 5
- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 description 5
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- ONVABDHFQKWOSV-UHFFFAOYSA-N 16-Phyllocladene Natural products C1CC(C2)C(=C)CC32CCC2C(C)(C)CCCC2(C)C31 ONVABDHFQKWOSV-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 2
- FCMCSZXRVWDVAW-UHFFFAOYSA-N 6-bromo-1-hexanol Chemical compound OCCCCCCBr FCMCSZXRVWDVAW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 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
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- ONVABDHFQKWOSV-YQXATGRUSA-N ent-Kaur-16-ene Natural products C1C[C@@H](C2)C(=C)C[C@@]32CC[C@@H]2C(C)(C)CCC[C@@]2(C)[C@@H]31 ONVABDHFQKWOSV-YQXATGRUSA-N 0.000 description 2
- 150000004254 ent-kauranes Chemical class 0.000 description 2
- UIXMIBNGPQGJJJ-UHFFFAOYSA-N ent-kaurene Natural products CC1CC23CCC4C(CCCC4(C)C)C2CCC1C3 UIXMIBNGPQGJJJ-UHFFFAOYSA-N 0.000 description 2
- -1 ent-kaurene diterpene Chemical class 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229940014800 succinic anhydride Drugs 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IVZWRQBQDVHDNG-KUIXFMFUSA-N ent-kaurane Chemical compound C([C@@]1(C)[C@@H]2CC3)CCC(C)(C)[C@H]1CC[C@]21C[C@H](C)[C@H]3C1 IVZWRQBQDVHDNG-KUIXFMFUSA-N 0.000 description 1
- UYNPPIDGSVPVSW-UHFFFAOYSA-N ent-kaurane Natural products CC1(O)CC23CCC4C(CCCC4(C)C(=O)O)C2C=CC1C3 UYNPPIDGSVPVSW-UHFFFAOYSA-N 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000003211 trypan blue cell staining Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of natural medicines and medicinal chemistry, and relates to a preparation method of a diterpene dimer hydrogen sulfide donor derivative and an application of the diterpene dimer hydrogen sulfide donor derivative in the aspect of tumor resistance. The hydrogen sulfide donor derivative of diterpene dimer and pharmaceutically acceptable salt thereof have the following general formula I, wherein n is1And n2As described in the claims and specification.
Description
Technical Field
The invention relates to the fields of natural medicines and medicinal chemistry, in particular to a diterpene dimer hydrogen sulfide donor derivative, a preparation method thereof and an application thereof in the aspect of tumor resistance. The invention also discloses a composition of the compounds and application of the compounds in preparing antitumor drugs.
Background
The natural-source, especially plant-source drugs can often provide novel and diverse lead compounds, and in vitro anti-tumor experiments show that ent-kaurene diterpene and dimers thereof exhibit strong anti-tumor activity, but the clinical application of the ent-kaurene diterpene and dimers thereof is greatly limited due to the defects of low bioavailability and the like. Structural modification and modification of ent-kaurane compounds are required to obtain more active and more bioavailable ent-kaurane compounds.
The invention takes the ent-kaurane diterpene oridonin as a lead compound, designs and synthesizes a class of diterpene dimer hydrogen sulfide donor derivatives, and tests the biological activity of the synthesized derivatives in the aspect of anti-tumor.
Disclosure of Invention
The invention aims to solve the technical problem of finding the oridonin hydrogen sulfide donor derivative with good antitumor activity and pharmaceutically acceptable salts thereof and further providing a pharmaceutical composition.
In order to solve the technical problems, the invention provides the following technical scheme:
the hydrogen sulfide donor derivative of diterpene dimer and the pharmaceutically acceptable salt thereof have the following structural general formula I:
wherein n is1、n2Is an integer of 1 to 8.
Preferably, n1、n2Is an integer of 2 to 6.
More preferably, n1Is 6; n is2Is 2 or 3.
The invention specifically discloses a diterpene dimer hydrogen sulfide donor derivative with the following structure and pharmaceutically acceptable salts thereof:
the derivative of the invention can be prepared by the following method:
the dithiocyclic compound 5- (4-hydroxyphenyl) -3H-1, 2-dithiole-3-thione (ADT-OH, 1) is reacted with bromohydrin (6-bromo-1-hexanol) to give ADT-OH derivative 2;
dissolving oridonin 3 in dichloromethane, sequentially adding triethylamine, DMAP and dianhydride (succinic anhydride or glutaric anhydride), and reacting at room temperature to obtain corresponding compounds 4a and 4 b;
dissolving the compound 4a or 4b in dichloromethane, and respectively carrying out esterification reaction with ADT-OH derivative 2 to obtain target derivatives 5a and 5 b.
The invention further provides a pharmaceutical composition, which comprises the hydrogen sulfide donor derivative of the diterpene dimer and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient.
Pharmacological tests prove that the oridonin 14-hydrogen sulfide donor dimer derivative, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof has a good anti-tumor effect and can be used for further preparing anti-tumor drugs.
The specific implementation mode is as follows:
example 1
Dissolving 68mg ADT-OH (0.3mmol) in anhydrous acetone, adding 117 μ L (0.9mmol) 6-bromohexanol and 125mg potassium carbonate (0.9mmol), refluxing for 8h, filtering to remove insoluble substances, and spin-drying the filtrate with silica gel column chromatography (petroleum ether: ethyl acetate)Ester 4:1) to give compound 2 orange. Then 96mg of oridonin 3(0.25mmol) was dissolved in 6ml of anhydrous dichloromethane, and 50mg of succinic anhydride (0.50mmol), 173. mu.L of triethylamine (1.25mmol) and a catalytic amount of DMAP were sequentially added and stirred at room temperature for 6 hours. The reaction was monitored by TLC and stopped when the reaction was complete or not continued. After washing with water, the mixture was separated, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4 a. 74.3mg of Compound 4a (0.16mmol) are dissolved in anhydrous dichloromethane, and 92mg of EDCI (0.48mmol), a catalytic amount of DMAP and 52mg of Compound 2(0.16mmol) are added successively and stirred at room temperature overnight. The reaction was monitored by TLC, after completion of the reaction about 20mL of water was added, extracted three times with 10mL of dichloromethane, the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel (dichloromethane: methanol 300:1) to give the target derivative 5a as an orange color with a yield of 40.2%.1H NMR(CDCl3,400MHz),δ(ppm):7.61,6.97(each 2H,d,JA＝JB＝8.7Hz,Ar-H),7.40(1H,s,8"-H),6.15(2H,s,17-CH2),6.09(2H,d,J＝10.2Hz,6-OH),5.91(2H,s,17-CH2),5.52(2H,s,14-CH),4.30(2H,d,J＝10.2Hz,20-CH2),4.08(6H,m,20-CH2,5'-CH2,),4.03,3.41(each 2H,t,J＝6.6Hz,10'-CH2),3.76(2H,m,6-CH),3.50(2H,dd,J＝11.2,5.7Hz,1-CH),3.16(2H,d,J＝9.7Hz,13-CH),2.58(8H,m,-CH2),1.99-1.71(10H,m,-CH2),1.70-1.41(18H,m,-CH2),1.12(12H,s,18-CH3,19-CH3)；13CNMR(CDCl3,100M Hz),δ(ppm):215.17,206.41,173.15,172.10,170.93,162.64,149.90,134.57,128.60(×2),120.24,115.48(×2),96.08,76.24,74.24,73.52,68.25,64.76,63.35,61.91,59.55,54.67,41.34,38.67,33.73,32.59,30.51,30.07,29.69,29.57,28.90,28.44,28.37,27.77,25.62,25.09,21.72,19.87；HRMS(ESI)m/z calcd forC69H90O19S3[M+H]+1319.5316,found 1319.5395。
Example 2
Derivative 5b was prepared as an orange solid with a yield of 37.1% according to the synthetic procedure of example 1.1H NMR(CDCl3,400MHz),δ(ppm):7.61,6.97(each 2H,d,JA＝JB＝8.8Hz,Ar-H),7.40(1H,s,8"-H),6.14(2H,s,17-CH2),6.06(2H,d,J＝10.2Hz,6-OH),5.87(2H,s,17-CH2),5.50(2H,s,14-CH),4.30(2H,d,J＝10.2Hz,20-CH2),4.10-4.01(8H,m,20-CH2,5'-CH2,10'-CH2),3.76(2H,t,J＝7.4Hz,6-CH),3.50(2H,dd,J＝11.1,5.6Hz,1-CH),3.41(2H,t,J＝6.7Hz,10'-CH2),3.17(2H,d,J＝9.9Hz,13-CH),2.60,2.24(each 2H,m,3'-CH2),2.33(8H,m,2'-CH2,4'-CH2),1.90(4H,t,J＝7.3Hz,-CH2),1.83(4H,m,-CH2),1.69-1.60(8H,m,-CH2),1.53-1.43(8H,m,-CH2),1.12(12H,s,18-CH3,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.10,206.42,173.23,172.78,171.35,162.55,149.87,134.54,128.60(×2),123.97,120.14,115.48(×2),96.17,76.40,74.12,73.47,68.25,64.43,63.40,61.87,59.66,54.62,41.34,38.65,33.73,33.56,33.10,32.57,30.51,30.06,28.92,28.50,27.77,25.63,25.13,21.69,19.82；HRMS(ESI)m/z calcd for C71H94O19S3[M+H]+1347.5629,found1347.5678。
The following are the results of pharmacological experiments with some of the compounds of the invention:
experimental equipment and reagent
Instrument clean bench (Sujing group Antai company)
Constant temperature incubator (Thermo electronic Corporation)
Enzyme-linked immunosorbent assay (BIO-RAD company)
Inverted biological microscope (Chongqing optical instrument factory)
Reagent cell culture Medium RPMI-1640, DMEM (high sugar) (GIBCO Co., Ltd.)
Fetal bovine serum (Hangzhou Sijiqing Co., Ltd.)
MTT (Biosharp company product)
Trypan blue (Solarbio company product)
DMSO (Sigma Co.)
Cell line human liver cancer cell HepG2, human cervical carcinoma cell SiHa, human breast cancer cell MCF-7, human colon cancer cell HCT-116, melanoma cell B16, human chronic myelogenous leukemia cell K562, human normal liver cell L-02, peripheral blood mononuclear cell PMBC
Experimental methods
Cell inhibitory activity test method
Cells were incubated at 37 ℃ with 5% CO2Culturing in an incubator with saturated humidity. The culture medium is RPMI1640 cell culture medium containing 10% heat-inactivated fetal calf serum, penicillin 100U/mL and streptomycin 100U/mL. The culture medium was changed for 48h, and after the cells were attached to the wall, they were digested with 0.25% trypsin for passage. The experimental cells are all in logarithmic growth phase, and trypan blue dye exclusion method shows cell viability>95％。
Taking a bottle of cells in a logarithmic phase, adding a digestive juice (0.125% trypsin and 0.01% EDTA) for digestion, and counting by 2-4 × 104cell/mL, preparing cell suspension, inoculating on 96-well plate, 100 μ L/well, and placing in constant temperature CO2The culture was carried out in an incubator for 24 hours. The medium was changed, and the test drugs (100. mu.L/well) were added at different concentrations and incubated for 72 hours. MTT solution was added to 96-well plates at 50. mu.L/well and incubated in an incubator for 4 hours. The supernatant was aspirated, DMSO (200. mu.L/well) was added, and the mixture was shaken on a flat plate shaker for 10 minutes at low speed. The test substances were examined at 3 concentrations (0.25. mu.M, 0.5. mu.M, 1. mu.M), and the cell inhibition rate was calculated at each concentration by measuring the absorbance at 490nm using an enzyme-linked immunosorbent assay.
The inhibition rate calculation method comprises the following steps:
results of the experiment
TABLE 1 examples IC for antiproliferative activity against 6 human cancer cell lines and 2 human normal cells50Value (μ M)
Pharmacological tests prove that the target derivative has better antitumor cell proliferation activity, has certain selectivity on tumor cells and normal cells, and can be used for further preparing antitumor drugs.
Claims (8)
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