CN110922415A

CN110922415A - Synthesis and application of novel anti-tumor active compound

Info

Publication number: CN110922415A
Application number: CN201911196798.0A
Authority: CN
Inventors: 何俊; 王贯; 罗小娇; 李蓉; 李峰
Original assignee: Sichuan University
Current assignee: Sichuan University
Priority date: 2019-11-29
Filing date: 2019-11-29
Publication date: 2020-03-27
Anticipated expiration: 2039-11-29
Also published as: CN110922415B

Abstract

The invention relates to synthesis and application of a novel anti-tumor active compound, belonging to the technical field of anti-tumor medicine. The technical problem solved by the invention is to provide a compound which is used for resisting colorectal cancer cells but not limited to the colorectal cancer cells. The compound includes a compound shown below or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt thereof has certain inhibitory activity on tumor cells, particularly HCT116 and Hep-G2, so that a new choice is provided for treating related tumors. The compound has simple structure and good activity, can be used as a leading compound of an anti-cancer medicament, and has good application prospect. Formula I

Description

Synthesis and application of novel anti-tumor active compound

Technical Field

The invention relates to the field of anti-tumor related medicaments. Specifically, the invention relates to a compound with an anti-tumor effect and anti-tumor activity thereof, and provides a basis for developing a medicament for preventing and treating tumors by a preparation method.

Background

Cancer is one of the diseases which have the greatest harm to human life health, a large number of people die from cancer every year, according to statistics, the total number of cancer deaths per year is 700 million people every year, more than 100 million people of tumor deaths per year in China, the incidence and mortality of tumors are also on the rise with the increase of population number and the acceleration of population aging, and the first cause of death of urban population, and the research and development of anticancer drugs are always hot spots of pharmaceutical research.

At present, for most cancer patients, clinically existing antitumor drugs have certain curative effect but have high cytotoxicity, and can inhibit the growth of normal cells of normal organisms to generate side effects while inhibiting cancer cells, and some side effects are even stronger than the curative effect. In addition, medical techniques have improved the effect of treating cancer only in the early stage of cancer in recent years, but have no effect on the advanced stage of cancer.

Therefore, the development of specific, highly effective and low-toxicity tumor-targeting drugs is a problem to be solved for the current anti-tumor

The invention discloses a novel anti-tumor drug, which can be used for targeted inhibition of colorectal cancer cells (HCT116) and human liver cancer cells (Hep-G2), but is not limited to the two tumor cells, has the most significant inhibition effect on HCT116, and has great significance for developing anti-tumor drugs and treating tumors.

Disclosure of Invention

The invention relates to a preparation method of a novel anti-tumor compound and application of the novel anti-tumor compound in anti-tumor drugs.

The invention aims to provide a pyridothiophene compound with tumor inhibition effect. The compound can effectively inhibit HCT116 colorectal cancer tumor cells, but is not limited to colorectal cancer cells.

The invention also aims to provide pharmaceutically acceptable salts of the pyridothiophene compounds.

The invention further aims to provide a preparation method of the pyridothiophene compound.

The invention further aims to provide application of the pyridothiophene compound.

Drawings

IC50 values for the compound of figure 1 on different tumor cell lines.

Detailed Description

The invention provides a pyridothiophene compound, which has a structure shown as the following formula I:

formula I

。

The reaction to prepare the compounds of the present invention is as follows:

。

intermediate I was prepared by adding morpholine (30.0 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (30.0 mmol), 2-cyanoacetamide (30.0 mmol) and sulfur (30.0 mmol) in absolute ethanol (200 mL). The resultant was refluxed for 8 hours. The suspension was cooled to ambient temperature and filtered through a pad of celite, washing with absolute ethanol (30 mL × 3). The combined filtrates were concentrated to dryness. The crude product was diluted with 95% ethanol (30 mL) and filtered to give the product as a white solid as shown in formula I with a yield of 83%.

Intermediate II was prepared and to a solution of intermediate I (10 mmol) and DIEA (20 mmol) in dichloromethane (60 mL) at room temperature was added dropwise a solution of the corresponding p-trifluoromethylbenzoyl chloride (1.1 eq) in dichloromethane (10 mL). The mixture was stirred for 8 hours and washed with water, saturated aqueous sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica eluting with dichloromethane/methanol (5-10%) to give the product in 63% yield as shown in figure ii.

Preparing an intermediate III, putting 100mL of methanol into a 250 mL round-bottom flask, cooling in a cold trap at 0 ℃ for 10 minutes, adding 10mmol of oxalyl chloride into the methanol solution, stirring for 10 minutes, adding an intermediate II, adding the intermediate II into a reaction system in batches, stirring for 30 minutes, moving to room temperature, detecting by TCL until the reaction intermediate disappears completely, performing vacuum rotary evaporation on the reaction system until the solution is about 1/2 with the existing volume, and adding saturated NaHCO dropwise₃Solution until the pH of the system is 7-8, and then extracting the system by using dichloromethane3 times, 3 times with water, 3 times with saturated saline, and finally, with Na₂SO₄Drying, standing for 30 min, collecting solution, vacuum rotary evaporating to small amount of solvent, silica gel column, petroleum ether: ethyl acetate = 5: 1, column chromatography, collection of the solution and vacuum spin-drying gave a white solid as shown in iii in 87% yield.

Preparing a final product IV, putting 10mL of dichloromethane into a 25mL round-bottom flask, adding DIEA (2mmol) and triethylamine (2mmol) at 0 ℃, stirring for 10 minutes, adding intermediate III (1.2mmol) and o-cyanobenzyl chloride (1mmol), stirring for 10 minutes, moving to room temperature for reaction for 12 hours, detecting by TCL until the reaction raw materials in the reaction liquid are not reduced any more, removing most of solvent under reduced pressure, and then using a silica gel column to prepare petroleum ether: ethyl acetate = 3: 1, column chromatography, collection of the solution and vacuum spin-drying gave a white solid as shown in iii in 67% yield.

In vitro cancer cell inhibition (MTT) tests show that the compound has obvious inhibition effect on various tumor cells such as human colorectal adenocarcinoma cells (HCT116), human breast cancer cell lines (MCF-7), human liver cancer cell lines (HepG2) and bladder cancer cell lines (RT 4). Especially, the inhibitor has stronger inhibiting effect on human colorectal adenocarcinoma cells (HCT116) and human liver cancer cell lines (HepG2), and the IC50 values are 9.8 uM and 26.5uM respectively. Therefore, the compound can be used for preparing a medicament for treating cancer and has good development and application prospects.

The application of the novel compound in inhibiting colorectal cancer cells, but not limited to colorectal cancer tumor cells, is disclosed for the first time, and because the skeleton type belongs to a brand new skeleton type, the possibility that other compounds give any revelation does not exist, the novel compound has prominent substantive characteristics, and simultaneously, the novel compound has significant inhibition on colorectal cancer (HCT116), thereby providing a new choice for treating related tumors.

The present invention will be described in further detail with reference to the following examples, but the scope of the present invention is not limited to the specific examples, but is defined by the claims.

¹H-NMR (400 MHz， DMSO-d6)，δ(ppm): 13.16 (1H， brs)， 8.32 (1H， d， J =8.2 Hz)， 8.09 (1H， d， J = 8.2 Hz)， 7.99 (1H， d， J = 8.0 Hz)， 7.91 (1H， d， J =8.4 Hz)， 7.83 (2H， d， J = 8.2 Hz)， 7.59 (2H， dd， J = 8.2， 3.1 Hz)， 3.70 (2H，s)， 3.64 (2H， s)， 2.89 (2H， brt， J = 4.7 Hz)， 2.72 (2H， brt， J = 4.7 Hz)。

¹³C-NMR (100 MHz， DMSO-d6)，δ(ppm): 168.0， 168.0， 161.8， 143.8， 142.6，136.5， 133.6， 133.6， 130.6， 128.6， 128.5， 128.5， 128.5， 126.6 (4.1 Hz)， 126.6(4.1 Hz)， 125.7 (169.0 Hz)， 124.5 (32.7 Hz)， 118.4， 116.8， 112.6， 59.1， 51.4，49.8， 25.8。

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof:

formula I

。

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: the structural formula is shown as formula I.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: application in preparing products for treating tumors.

4. Use according to claim 3, characterized in that: the tumor comprises colorectal cancer cells (HCT116), breast cancer cell lines (MCF-7), human liver cancer cell lines (HepG2) and bladder cancer cell lines (RT4), but is not limited to the tumor cells.

5. Use according to claim 4, characterized in that: has certain anti-tumor activity, and the inhibition rate of colorectal cancer cells HCT116 cells and liver cancer cells (HepG2) reaches a significant level (p < 0.05).