CN107638426B - Application of thiazole compound in preparation of medicine for treating tumors - Google Patents
Application of thiazole compound in preparation of medicine for treating tumors Download PDFInfo
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- CN107638426B CN107638426B CN201710952738.1A CN201710952738A CN107638426B CN 107638426 B CN107638426 B CN 107638426B CN 201710952738 A CN201710952738 A CN 201710952738A CN 107638426 B CN107638426 B CN 107638426B
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Abstract
The invention relates to the technical field of medicines, in particular to application of thiazole compounds shown in a formula I or pharmaceutically acceptable salts thereof in preparing medicines for treating tumors. Wherein, the definition of each substituent is described in the specification.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of thiazole compounds in preparing a medicine for treating tumors.
Background
Cancer is a leading cause of morbidity and mortality worldwide. Chemotherapy of tumors is one of the most important therapeutic strategies. The occurrence and the metastasis of tumors are caused by uncontrolled apoptosis, the apoptosis is related to the activation, the expression and the regulation of a series of proteins, and a Bcl-2 protein family is the most important regulatory protein in an apoptosis protein family.
PUMA is an important apoptosis-promoting protein in Bcl-2 protein family, and can competitively bind with anti-apoptosis protein, release BAX and the like, and induce apoptosis through dimerization of the latter. In the traditional radiotherapy and chemotherapy of tumor treatment, the PUMA is directly increased, the apoptosis promoting function of the PUMA is strong, and the PUMA plays a role in playing a role in a plurality of apoptosis ways.
Disclosure of Invention
Therefore, the invention provides the application of thiazole compounds shown in the formula I or pharmaceutically acceptable salts thereof in preparing medicaments for treating tumors.
Preferably, the tumor comprises nasopharyngeal carcinoma, leukemia, clear cell carcinoma of the kidney, high metastatic lung carcinoma, glioblastoma, rhabdomyosarcoma, ovarian carcinoma, lung carcinoma, melanoma, neuroblastoma, gastric adenocarcinoma, cervical carcinoma, colorectal adenocarcinoma, squamous carcinoma of the tongue, Burkitt's lymphoma, prostate carcinoma, esophageal carcinoma, clear cell carcinoma of the ovary, kidney carcinoma, gallbladder carcinoma, high metastatic liver carcinoma, endometrial adenocarcinoma, liver carcinoma, small intestine carcinoma, human brain glioma, fibrosarcoma, T-lymphocytic leukemia, gastric carcinoma, oral epidermoid carcinoma, lung adenocarcinoma, breast carcinoma, B-lymphocytoma, colon carcinoma, cervical squamous carcinoma, hepatic ascites, cutaneous melanoma, thyroid squamous carcinoma, rhabdomyosarcoma, glioma, epidermoid carcinoma of the larynx, transitional cell carcinoma of the bladder, salivary gland adenoid cystic carcinoma and lung adenocarcinoma.
More preferably, the tumor is colon cancer, cervical cancer, ovarian cancer, lung cancer, breast cancer or liver cancer.
The thiazole compound of the formula I or a pharmaceutically acceptable salt thereof is as defined below.
Wherein:
a is C5～C10Aryl, or 5-to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S;
specifically, a may be:
preferably, A is C5～C6Aryl, or 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S;
more preferably, a is phenyl or pyridazinyl.
E is a hetero compound containing 0 to 2 hetero atoms selected from N, O and S5-to 6-membered saturated or unsaturated alicyclic ring of atom, -C3～C6Alkyl-, -NH-C1～C3Alkyl-, -O-C1～C3Alkyl-, -C1～C3alkyl-NH-C1～C3Alkyl-, -C1～C3alkyl-O-C1～C3Alkyl-, -NH-C1～C3alkyl-NH-, -O-C1～C3alkyl-O-;
specifically, E may be:
preferably, E is a 5-6 membered saturated aliphatic ring containing 0-2 heteroatoms selected from N, O and S;
more preferably, E is piperazinyl or piperidinyl.
Y is O, S, NH or CH2(ii) a Preferably, Y is O.
R1Is H, C1～C6Alkyl radical, C1～C6Alkoxy, halogen (fluorine, chlorine, bromine, iodine), -OH, -NH2Or 1 to 3R3Substituted C5～C6Aryl or 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N and O; r3Is H, C1～C6Alkyl radical, C1～C6Alkoxy, halogen (fluorine, chlorine, bromine, iodine), -OH, -NH2；
Specifically, R1Can be as follows: H. c1～C6Alkyl radical, C1～C6Alkoxy, halogen (fluorine, chlorine, bromine, iodine), -OH, -NH2、
R2Is H, -OH, -NH2、-SH、-COOH、-CONH2、-SO2NH2、-SO3H、-CH(OH)-CH2-OH。
n is an integer of 1-5; in particular, n may be 1, 2, 3, 4 or 5.
The "aryl" refers to an aromatic group that does not contain heteroatoms;
the "heteroaryl" refers to an aromatic group containing a heteroatom;
the "heterocyclic group" means a non-aromatic group containing a hetero atom;
the "alkyl group" includes a straight chain or branched chain alkyl group.
In the above description of the invention, A, E, Y, R1、R2And n may be combined with any of the other general, specific, preferred, and more preferred ranges.
Preferably, the thiazole compound of the formula I or the pharmaceutically acceptable salt thereof is the following thiazole compound of the formula II:
wherein, A, E, R1、R2And n is as defined above.
In one embodiment, the thiazole compound of the formula I or the pharmaceutically acceptable salt thereof or the thiazole compound of the formula II or the pharmaceutically acceptable salt thereof is the following compound 1 to 12 or a pharmaceutically acceptable salt thereof:
in one embodiment, the thiazole compound of the formula I or a pharmaceutically acceptable salt thereof or the thiazole compound of the formula II or a pharmaceutically acceptable salt thereof is the following compound or a pharmaceutically acceptable salt thereof:
the preparation method of the thiazole compound with the formula I or the pharmaceutically acceptable salt thereof comprises the following steps:
compound 21, an alcohol (e.g., methanol) and an acid (e.g., glacial acetic acid) are added to a vessel under N2Under protection, adding a compound 22 and a compound 23, refluxing in an oil bath, precipitating a solid in an ice bath after the reaction is finished, performing suction filtration, washing, and purifying by silica gel column chromatography to obtain the compound;
wherein, A, E, R1、R2、R3And n is as defined above.
Thiazole compounds of formula I of the present invention or pharmaceutically acceptable salts thereof are described in patent document application No. CN 201610242882.1. The entire contents of this patent document are incorporated by reference into this application.
In addition, the invention provides a pharmaceutical composition for treating tumors, which contains the thiazole compound shown in the formula I or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
The thiazole compound of the formula I or the pharmaceutically acceptable salt thereof can promote the apoptosis of tumor cells and block the apoptosis of normal cells, and can generate good treatment effect of promoting the apoptosis of the tumor cells and protection effect of inhibiting the apoptosis of the normal cells. The invention provides a novel idea and strong evidence for the application of a small molecular compound in tumor chemotherapy drugs, and is expected to become a high-efficiency, low-toxicity and stable clinical tumor treatment drug.
Detailed Description
The present invention will be described below with reference to examples, but the present invention is not limited thereto.
Experimental example 1 Activity inhibition test of Compounds 1 to 12 on tumor cells
Adding 2mL of RPMI1640 and DMEM high-glucose complete culture medium into cell lines frozen with A2780 (human ovarian cancer cells), MCF-7 (human breast cancer cells), A549 (human lung cancer cells), SMMC-7721 (human liver cancer cells), Hela (human cervical cancer cells) and HcT-116 (human colon cancer cells), respectively, centrifuging at 1000rpm for 3min, discarding supernatant, and removing supernatantThen 3mL of the corresponding complete medium was added, 5% CO at 37 ℃2When the cells grow to the logarithmic growth phase, the cell density is adjusted to 5 × 104cells/mL, inoculated into 96-well cell culture plates, 150. mu.L per well, 3 multiple wells per concentration gradient, MTT detection at different time points, 37 ℃, 5% CO2Cultured to 60% density. Diluting the compounds 1-12 to 200. mu.M, 100. mu.M, 50. mu.M, 25. mu.M, 12.5. mu.M and 6.25. mu.M respectively with complete medium; treatment was administered in groups of experiments. After 24h incubation, 15. mu.L of MTT, 37 ℃ C., 5% CO was added to each well2Culturing in incubator for 3-4h in dark place. The well was aspirated, 200. mu.L DMSO was added, and the mixture was shaken on a shaker at room temperature for 10 min. OD values at the same time point were measured at a wavelength of 492nm using a microplate reader, and the influence of cell proliferation was analyzed using the measured OD values.
TABLE 1 IC for inhibition of tumor cell activity by compounds 1-1250(μM)
| Compound (I) | A2780 | MCF-7 | A549 | SMMC-7721 | Hela | HCT116 |
| 1 | 24.6 | 24.8 | 43.7 | 11.5 | 38.9 | 25.6 |
| 2 | 47.6 | 44.2 | 93.9 | 44.1 | 72.3 | 78.5 |
| 3 | 33.1 | 483 | 75.3 | 20.7 | 332 | 12.5 |
| 4 | 0.06 | 46.1 | 37.9 | 97.6 | 95.4 | 76.3 |
| 5 | 50.2 | 66 | 40.1 | 721 | 61.6 | 50 |
| 6 | 26.4 | 923 | 87.8 | 65.2 | 11.6 | 6.28 |
| 7 | 62 | 73.8 | 76.9 | 70.6 | 258 | 631 |
| 9 | 91.5 | 58 | 89.9 | 99.5 | 5.64 | 18.3 |
| 10 | 56.2 | 90.5 | 24.6 | 29.5 | 86.2 | 59.4 |
| 11 | 15.2 | 35.3 | 0.89 | 54.4 | 53.4 | 87.4 |
| 12 | 399 | 671 | 228 | 44.3 | 61.3 | 125 |
As can be seen from the above table, the compounds 1-12 have good inhibitory effect on tumor cells on MTT. Among them, compound 4 had the best effect on human ovarian cancer cells a 2780. The compound 11 has good inhibitory activity on human lung cancer cell A549. These compounds show variable effects on selected tumor cells, IC50Less than 100 μ M is common.
Experimental example 2 apoptosis Activity of Compounds 1 to 12 against pAd-PUMA-infected DLD-1 cells
This experiment further demonstrated the apoptotic activity of the compounds of the invention on pAd-PUMA infected DLD-1 cells, as detected using the Caspase-Glo 3/7 method. DLD-1 cells in CO25% CO at 37 ℃ in an incubator2The cell density was maintained at about 20%, and the cells were infected with pAd-PUMA after 24 hours of culture. The MOI of the virus was 10 and the amount used was 0.01. mu.l. After 24h of infection, the compounds were formulated in 10mM DMSO solutions and added at the pre-set concentrations. After further culturing for 24h, 25. mu.l of Caspase-Glo 3/7 reagent is added, and the plate is rotated for 30s at 300-500 rpm to mix the reagents in the plate. Culturing for 2h under the same condition, and detecting by chemiluminescence method. IC is obtained through experiments on apoptosis inhibition effect of compounds 1-12 of the invention on pAd-PUMA infected DLD-1 cells50The results are shown in Table 2.
TABLE 2 apoptosis inhibitory Activity IC of Compounds 1-12 against pAd-PUMA-infected DLD-1 cells50
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | 57.42μM | 7 | 37.89μM |
| 2 | 38.93μM | 8 | 158.6μM |
| 3 | 25.98μM | 9 | 11.7mM |
| 4 | 43.89μM | 10 | 7.14mM |
| 5 | 12.87μM | 11 | 2.97mM |
| 6 | 1.89mM | 12 | 387.4μM |
The PUMA over-expression cell experiment and enzyme level affinity activity research show that the compound has strong anti-apoptosis effect of targeting PUMA protein, and can be applied to the over-apoptosis of PUMA protein-related cells to generate effective protection against the damage of normal cells after tumor radiotherapy and chemotherapy.
Claims (3)
1. The application of thiazole compounds of formula II or pharmaceutically acceptable salts thereof in preparing medicaments for treating tumors:
wherein:
a is C5～C6Aryl, or 5-6 membered heteroaryl containing 1-2 heteroatoms selected from N, O and S;
e is
R1Is H, C1～C6Alkyl radical, C1～C6Alkoxy, halogen, or 1 to 3R3Substituted C5～C6An aryl group; r3Is H;
R2is-OH or-SH;
n is an integer of 1-5;
and the thiazole compounds of the formula II do not include the following compounds:
2. the use according to claim 1, wherein the tumor is colon cancer, cervical cancer, ovarian cancer, lung cancer, breast cancer or liver cancer.
3. The use according to claim 1 or 2, wherein the thiazole compound of the formula ii or the pharmaceutically acceptable salt thereof is the following compound 1 to 5, 7:
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| CN2016110625342 | 2016-11-28 | ||
| CN201611062534 | 2016-11-28 |
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| CN108148058B (en) * | 2018-02-08 | 2021-03-16 | 中国人民解放军第四军医大学 | 4- (2-mercaptothiadiazole) substituted pyrimidine derivative, and preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075372A1 (en) * | 2008-12-22 | 2010-07-01 | The Trustees Of Columbia University In The City Of New York | Inhibitors of mre11, rad50 and/or nbs1 |
| CN107304192A (en) * | 2016-04-19 | 2017-10-31 | 中国人民解放军第四军医大学 | One class PUMA inhibitor and its production and use |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010075372A1 (en) * | 2008-12-22 | 2010-07-01 | The Trustees Of Columbia University In The City Of New York | Inhibitors of mre11, rad50 and/or nbs1 |
| CN107304192A (en) * | 2016-04-19 | 2017-10-31 | 中国人民解放军第四军医大学 | One class PUMA inhibitor and its production and use |
Non-Patent Citations (1)
| Title |
|---|
| PUMA作为细胞保护和肿瘤治疗靶点的研究进展;周长辉 等;《生命科学》;20100630;第22卷(第6期);556-560 * |
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