Application of 1, 3, 4-thiadiazole peptide deformylase inhibitor in preparation of anti-cancer drugs

Abstract

The invention discloses an application of a 1, 3, 4-thiadiazole peptide deformylase inhibitor in preparation of anti-cancer drugs, and the structural general formula of the 1, 3, 4-thiadiazole peptide deformylase inhibitor is # imgabs0. The 1, 3, 4-thiadiazole peptide deformylase inhibitor provided by the invention has the characteristics of small toxicity and high anti-cancer activity, and can be used for preparing anti-cancer drugs. The preferable compound of the inhibitor shows good killing capability on cancer cells over-expressed by various peptide deformylase, and can be further used for preparing anti-cancer drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of new medical uses of 1,3,4-thiadiazole peptide deformylase inhibitors, and specifically relates to the use of 1,3,4-thiadiazole peptide deformylase inhibitors in the preparation of anticancer drugs. Background Art

[0002] Cancer, as one of the leading causes of death worldwide, has attracted widespread attention in the past few decades, and various treatments including chemotherapy, radiotherapy, surgical resection, phototherapy, and immunotherapy have been developed. However, despite significant progress in cancer detection, prevention, and treatment, the incidence and mortality of cancer are still rising rapidly. Therefore, new drugs with novel anti-tumor strategies are urgently needed to prolong patient survival.

[0003] Peptide deformylase (PDF) is a metalloproteinase widely present in bacteria. During the protein synthesis process of prokaryotes, the start codon encodes the formation of formylmethionine. However, the nascent polypeptide removes the N-terminal formyl group under the catalysis of peptide deformylase, and then removes the methionine residue through methionine aminopeptidase (MAP) to finally synthesize active protein. Therefore, by inhibiting peptide deformylase to stagnate protein synthesis at the stage of removing the N-terminal formyl group, the growth of bacteria can be effectively inhibited. In 2003, human peptide deformylase (HsPDF) was cloned and identified by Davida.Scheinberg and ThierryMeinnel. HsPDF was found to be located in mitochondria and is the cause of deformylation of 13 mitochondrial DNA (mtDNA) encoded proteins. N-formylation is considered to be a necessary condition for mitochondrial protein translation because the initiation factor recognizes "Formyl-Met-tRNA" as the initiator tRNA, but not Met-tRNA. HsPDF is overexpressed in a variety of cancer cells, including lung cancer, breast cancer, and colon cancer. Studies have found that Actionin can significantly reduce the proliferation of these cancer cells by inhibiting or knocking down HsPDF expression through siRNA, but has no obvious toxic side effects on normal cells. These results show that HsPDF plays an important role in maintaining mitochondrial function and cell apoptosis. By inhibiting HsPDF, the proliferation of cancer cells can be effectively inhibited, achieving the effect of treating cancer.

[0004] Based on the above principles, some research teams have carried out research on anticancer drugs targeting HsPDF in recent years. In addition to the natural product actinonin, which has been proven to have certain anti-tumor activity, the Lee team, the Djaballah team of Professor Sloan-Kettering Cancer Institute, the Gao team of Xuzhou Medical University, and the Hu Wenhao team of Sun Yat-sen University have designed a series of four types of peptide deformylase inhibitors with different anti-cancer activities by modifying the structure of actinonin. The corresponding structures are as follows:

[0005]

[0006] The patent document with application publication number CN117886808A discloses a 1,3,4-thiadiazole peptide deformylase inhibitor and its preparation and application. It specifically discloses that the 1,3,4-thiadiazole peptide deformylase inhibitor can effectively inhibit bacterial protein synthesis, thereby achieving the purpose of sterilization. This type of compound exhibits excellent inhibitory activity against Gram-positive resistant bacteria, especially the clinically difficult methicillin-resistant Staphylococcus aureus (MRSA); in addition, the 1,3,4-thiadiazole peptide deformylase inhibitor also exhibits inhibitory activity against Gram-negative resistant bacteria, especially against the drug-resistant Acinetobacter baumannii known as the "super bacteria", and its antibacterial activity reaches 0.5μg / mL. However, the patent document does not have any relevant records on the 1,3,4-thiadiazole peptide deformylase inhibitor in inhibiting the proliferation of cancer cells. Summary of the invention

[0007] The technical problem solved by the present invention is to provide the use of 1,3,4-thiadiazole peptide deformylase inhibitors in the preparation of anticancer drugs, wherein the preferred compounds of the inhibitors show good killing ability against cancer cells overexpressing various peptide deformylases.

[0008] The present invention adopts the following technical solution to solve the above technical problems: application of 1,3,4-thiadiazole peptide deformylase inhibitor in the preparation of anticancer drugs, wherein the general structural formula of the 1,3,4-thiadiazole peptide deformylase inhibitor is:

[0009]

[0010] Where R is

[0011]

[0012] It is further defined that the anticancer drug comprises a 1,3,4-thiadiazole peptide deformylase inhibitor and a pharmaceutically acceptable salt thereof.

[0013] It is further defined that the anticancer drug is used to inhibit the proliferation of cancer cells, wherein the cancer cells are preferably MCF-7 cells, Hela cells and / or A549 cells.

[0014] It is further defined that the 1,3,4-thiadiazole peptide deformylase inhibitor is preferably the following compound:

[0015]

[0016] The present invention has the following advantages and beneficial effects: the 1,3,4-thiadiazole peptide deformylase inhibitor provided by the present invention has the characteristics of low toxicity and high anticancer activity, and the preferred compound of the inhibitor shows good killing ability against MCF-7 cells, Hela cells and / or A549 cells, which are cancer cells overexpressing multiple peptide deformylases, and can be further used to prepare anticancer drugs. DETAILED DESCRIPTION

[0017] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0018] Example

[0019] The cell concentration was 3.5 × 10 4 MCF-7 / Hela / A549 cancer cells with a concentration of 100 μL / mL were inoculated in a 96-well plate, with 100 μL in each well, and 100 μL RPMI-1640 medium was added to the blank wells. The plates were cultured in a 37°C, 5% CO2 incubator for 24 hours. The experimental group then replaced the culture medium with new culture medium containing different concentrations of the tested samples, with 3 replicates for each concentration, and the control group replaced the culture medium with an equal volume of solvent. The culture was continued for 72 hours, and MTT was added for another 4 hours. After DMSO was dissolved, the absorbance A value of each well was detected at a wavelength of 490 nm using a full-wavelength multifunctional reader. The results showed that some compounds in the 1,3,4-thiadiazole peptide deformylase inhibitors had a good inhibitory effect on the tested cancer cells, and their IC 50 As shown in Table 1.

[0020]

[0021] Table 1 In vitro anticancer activity of thiadiazole peptide deformylase inhibitors

[0022]

[0023]

[0024] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for illustrating the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. Application of 1,3,4-thiadiazole peptide deformylase inhibitor in the preparation of anticancer drugs, wherein the general structural formula of 1,3,4-thiadiazole peptide deformylase inhibitor is: Where R is 2. The use according to claim 1, characterized in that: The anticancer drugs include 1,3,4-thiadiazole peptide deformylase inhibitors and pharmaceutically acceptable salts thereof.

3. The use according to claim 1, characterized in that: The anticancer drug is used to inhibit the proliferation of cancer cells, wherein the cancer cells are preferably MCF-7 cells, Hela cells and / or A549 cells.

4. The use according to claim 1, characterized in that: The 1,3,4-thiadiazole peptide deformylase inhibitor is preferably the following compound:

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