CN110964033A - Oridonin 14-position hydrogen sulfide donor derivative and preparation method and application thereof - Google Patents
Oridonin 14-position hydrogen sulfide donor derivative and preparation method and application thereof Download PDFInfo
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- CN110964033A CN110964033A CN201911279214.6A CN201911279214A CN110964033A CN 110964033 A CN110964033 A CN 110964033A CN 201911279214 A CN201911279214 A CN 201911279214A CN 110964033 A CN110964033 A CN 110964033A
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- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
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Abstract
The invention relates to the field of natural medicines and medicinal chemistry, and relates to an oridonin 14-hydrogen sulfide donor derivative, a preparation method thereof and an application thereof in the aspect of tumor resistance. The structure of the oridonin hydrogen sulfide donor derivative and the pharmaceutically acceptable salt thereof is shown as the general formula I, wherein n is1And n2As described in the claims and specification.
Description
Technical Field
The invention relates to the field of natural medicines and medicinal chemistry, in particular to an oridonin 14-hydrogen sulfide donor derivative, a preparation method thereof and a new application thereof in the aspect of tumor resistance. The invention also discloses a pharmaceutical composition of the compounds and application of the compounds in preparing antitumor drugs.
Background
Oridonin is a natural organic compound of ent-kaurene diterpenoid separated from Rabdosia (Rabdosia) plants in Labiatae, has the functions of resisting cell proliferation, inhibiting synthesis of DNA, RNA and protein of cancer cells, inducing apoptosis, resisting mutation, blocking β -receptor and the like, and is discovered by scholars at home and abroad to have certain treatment effects on esophageal cancer, gastric cancer, liver cancer, lung cancer, nasopharyngeal cancer, colon cancer, bladder cancer, cervical cancer and leukemia in 30 years along with the deep research on oridonin research, so the pharmacological activity research of oridonin attracts more attention and has wide development prospect.
The invention takes the oridonin as a lead compound, designs and synthesizes the oridonin 14-position hydrogen sulfide donor derivative, and tests the bioactivity of the synthesized derivative 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 oridonin 14-position hydrogen sulfide donor derivative 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, n1、n2Is 2 or 3.
The invention also discloses an oridonin 14-position hydrogen sulfide donor derivative with the structure shown as follows and pharmaceutically acceptable salts thereof:
the derivative of the invention can be prepared by the following method:
the dithioheterocyclic compound 5- (4-hydroxyphenyl) -3H-1, 2-dithiole-3-thione (ADT-OH, 1) reacts with bromohydrin (2-bromoethanol, 3-bromo-1-propanol) to obtain ADT-OH derivatives 2a and 2 b;
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 2a or 2b to obtain a target compound 5 a-d.
The invention further provides a pharmaceutical composition, which comprises the oridonin 14-position hydrogen sulfide donor derivative, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients.
Pharmacological tests prove that the oridonin 14-hydrogen sulfide donor derivative, the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof has good anti-tumor effect and can be used for further preparing anti-tumor drugs.
The specific implementation mode is as follows:
example 1
Dissolving 45mg of ADT-OH (0.2mmol) in anhydrous acetone, adding 43 mu L of 2-bromoethanol (0.6mmol) and 83mg of potassium carbonate (0.6mmol), refluxing for 8h, filtering after the reaction is finished, and performing spin-drying silica gel column chromatography on the filtrate (petroleum ether: ethyl acetate: 4:1) to obtain an orange-red compound 2 a. Then 91mg of oridonin (0.25mmol) was dissolved in 6mL of anhydrous dichloromethane, 50mg of succinic anhydride (0.50mmol), 173. mu.L of triethylamine (1.25mmol), and a catalytic amount of DMAP were added, and the mixture was stirred at room temperature for 6 hours. Monitoring the reaction by TLC, and waiting for the reactionThe reaction was stopped when the reaction was complete or not continued. After washing with water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 4 a. 74mg of compound 8a (0.16mmol) are dissolved in anhydrous dichloromethane, and 92mg of EDCI (0.48mmol), a catalytic amount of DMAP and 43mg of compound 7a (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 compound 5a as an orange color with a yield of 33.8%.1H NMR(CDCl3,400MHz),δ(ppm):7.63,7.01(each2H,d,JA＝JB＝8.6Hz,Ar-H),7.40(1H,s,8"-H),6.15(1H,s,17-CH2),6.05(1H,d,J＝10.7Hz,6-OH),5.89(1H,s,17-CH2),5.51(1H,s,14-CH),4.46(2H,m,5'-CH2),4.29,4.06(each 1H,d,J＝10.5Hz,20-CH2),4.24(2H,t,J＝4.6Hz,6'-CH2),3.75(1H,d,10.0Hz,6-CH),3.49(1H,dd,J＝11.1,5.7Hz,1-CH),3.14(1H,d,J＝9.8Hz,13-CH),2.65(2H,m,3'-CH2),2.59(2H,m,2'-CH2),2.54-2.41(2H,m,-CH2),2.22,1.97(each 1H,m,-CH2),1.93(2H,m,-CH2),1.80-1.52(2H,m,-CH2),1.46(2H,m,-CH2),1.11(3H,s,18-CH3),1.10(3H,s,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.20,206.36,172.85,171.96,170.76,161.77,149.90,134.82,128.63(×2),124.64,120.28,115.64(×2),96.05,76.18,74.33,73.49,66.15,63.37,62.73,61.93,59.49,54.68,41.33,38.65,33.73,32.61,30.53,30.06,29.69,29.53,28.83,21.75,19.89；HRMS(ESI)m/z calcd for C35H40O10S3[M-H]-715.1706,found715.1731。
Example 2
Compound 5b was prepared as an orange solid with a yield of 32.6% according to the synthetic method of example 1.1H NMR(CDCl3,400MHz),δ(ppm):7.63,7.00(each 2H,d,JA＝JB＝8.0Hz,Ar-H),7.42(1H,s,8"-H),6.14(1H,s,17-CH2),6.06(1H,d,J＝8.5Hz,6-OH),5.90(1H,s,17-CH2),5.51(1H,s,14-CH),4.30(3H,m,5'-CH2,20-CH2),4.10(3H,m,7'-CH2,20-CH2),3.75(1H,m,6-CH),3.50(1H,dd,J＝11.1,5.5Hz,1-CH),3.12(1H,d,J＝9.7Hz,13-CH),2.58(4H,m,-CH2),2.16(2H,t,J＝5.8Hz,2'-CH2),1.96,1.76(each 1H,m,-CH2),1.70-1.43(6H,m,-CH2),1.11(6H,s,18-CH3,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.12,206.37,173.16,172.04,170.90,162.23,149.87,134.63,128.61(×2),124.21,120.27,115.55(×2),96.05,76.12,74.32,73.43,64.87,63.42,61.94,61.31,59.51,54.67,41.34,41.30,38.63,33.73,32.61,30.51,30.06,29.54,28.86,28.49,21.75,19.93；HRMS(ESI)m/z calcd for C36H42O10S3[M-H]-729.1862,found 729.1890。
Example 3
Compound 5c was prepared as an orange solid with a yield of 31.8% according to the synthetic method of example 1.1H NMR(CDCl3,400MHz),δ(ppm):7.63,6.99(each 2H,d,JA＝JB＝8.8Hz,Ar-H),7.40(1H,s,8"-H),6.13(1H,s,17-CH2),6.05(1H,d,J＝8.6Hz,6-OH),5.87(1H,s,17-CH2),5.50(1H,s,14-CH),4.30,4.07(each 1H,d,J＝10.4Hz,20-CH2),4.44,4.23(each 2H,t,J＝4.4Hz,6'-CH2,7'-CH2),3.74(1H,m,6-CH),3.50(1H,dd,J＝11.2,5.7Hz,1-CH),3.15(1H,d,J＝9.8Hz,13-CH),2.60,2.24(each 1H,m,3'-CH2),2.42-2.33(4H,m,2'-CH2,4'-CH2),1.94(4H,m,-CH2),1.11(3H,s,18-CH3),1.10(3H,s,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.19,206.38,172.88,172.57,171.27,161.75,149.86,134.80,128.66(×2),124.63,120.19,115.58(×2),96.15,76.33,74.16,73.48,66.15,63.41,62.38,61.88,59.60,54.62,41.34,41.31,38.64,33.73,33.44,32.89,32.58,30.52,30.07,29.69,21.70,19.83；HRMS(ESI)m/z calcd for C36H42O10S3[M-H]-729.1862,found 729.1889。
Example 4
Compound 5d was prepared as an orange solid with a yield of 30.2% according to the synthetic method of example 1.1H NMR(CDCl3,400MHz),δ(ppm):7.62,6.98(each 2H,d,JA＝JB＝8.7Hz,Ar-H),7.40(1H,s,8"-H),6.13(1H,s,17-CH2),6.05(1H,s,6-OH),5.87(1H,s,17-CH2),5.50(1H,s,14-CH),4.30,4.07(each 1H,d,J＝10.8Hz,20-CH2),4.27,4.10(each 2H,t,J＝6.4Hz,-CH2),3.75(1H,brs,6-CH),3.50(1H,dd,J＝11.1,5.7Hz,1-CH),3.15(1H,d,J＝9.8Hz,13-CH),2.60,2.25(each1H,m,3'-CH2),2.34(4H,m,-2'-CH2,4'-CH2),2.15,1.90(each 2H,m,-CH2),1.80-1.42(8H,m,-CH2),1.12(3H,s,18-CH3),1.11(3H,s,19-CH3)；13C NMR(CDCl3,100M Hz),δ(ppm):215.13,206.38,173.10,172.63,171.28,162.15,149.86,134.66,128.64(×2),124.27,120.18,115.49(×2),96.17,76.34,74.15,73.47,64.82,63.42,61.88,61.06,59.61,54.62,41.34,41.32,38.64,33.74,33.53,33.03,32.58,30.52,30.07,29.70,28.44,21.71,19.84；HRMS(ESI)m/z calcd for C37H44O10S3[M-H]-743.2019,found 743.2034。
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 breast cancer cell MCF-7, human colon cancer cell HCT-116, melanoma cell B16 or M14, 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:
relative OD value of drug sensitive well (absolute OD value of drug sensitive well) — absolute OD value of blank control well
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)
1. Oridonin 14-position hydrogen sulfide donor derivatives represented by general formula I and pharmaceutically acceptable salts thereof:
wherein n is1、n2Is an integer of 1 to 8.
2. The oridonin 14-position hydrogen sulfide donor derivative of claim 1 and pharmaceutically acceptable salts thereof:
wherein n is1、n2Is an integer of 2 to 6.
3. The oridonin 14-position hydrogen sulfide donor derivative of claim 1 or 2, and pharmaceutically acceptable salts thereof:
wherein n is1、n2Is 2 or 3.
4. A pharmaceutical composition comprising a therapeutically effective amount of a derivative according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
5. The preparation method of oridonin 14-hydrogen sulfide donor derivatives and pharmaceutically acceptable salts thereof shown in the general formula I in claim 1, which comprises the following steps:
(1) the dithio-heterocyclic compound 5-p-hydroxyphenyl-3H-1, 2-dithio-cyclopentene-3-thioketone reacts with bromohydrin to obtain ADT-OH derivative 2;
(2) dissolving oridonin 3 in dichloromethane, sequentially adding triethylamine, DMAP and dianhydride, and reacting at room temperature to obtain a corresponding compound 4;
(3) dissolving the compound 4 in dichloromethane, and respectively carrying out esterification reaction with ADT-OH derivatives 2 to obtain a target compound 5;
6. the use of oridonin 14-position hydrogen sulfide donor derivatives and pharmaceutically acceptable salts thereof as claimed in any of claims 1-3 in the manufacture of a medicament for the treatment of neoplastic diseases.
7. Use of the pharmaceutical composition of claim 4 for the preparation of a medicament for the treatment of a neoplastic disease.
8. The use of claim 6 or 7, wherein the tumor is liver cancer, breast cancer, colon cancer, melanoma or leukemia.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574172A (en) * | 2020-12-14 | 2021-03-30 | 杭州海醍思医疗科技有限公司 | Gallic acid hydrogen sulfide derivative, preparation method and medical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102850369A (en) * | 2011-06-29 | 2013-01-02 | 中国药科大学 | Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102850369A (en) * | 2011-06-29 | 2013-01-02 | 中国药科大学 | Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| HAONAN LI，等: "Hydrogen sulfide donating ent-kaurane and spirolactone-type 6,7-seco-ent-kaurane derivatives: Design, synthesis and antiproliferative properties", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574172A (en) * | 2020-12-14 | 2021-03-30 | 杭州海醍思医疗科技有限公司 | Gallic acid hydrogen sulfide derivative, preparation method and medical application thereof |
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