Synthesis And Activity Of Indole-benzoheterocyclic VEGFR-2 Inhibitors

Malignant tumor is the disease with the highest mortality rate in the world,which is a serious threat to h?man life and health.However,there is still a lack of effective antitumor drugs.Targeting drug is an important research direction of antitumor drugs,among which vascular targeting is a research hotspot.Tumor angiogenesis is mediated by VEGF/VEGFR signaling pathway.VEGFR-2 is the most important receptor of VEGF.Inhibition of VEGFR-2 tyrosine kinase activity can effectively block tumor angiogenesis signal transduction,inhibit vascular growth,and thus inhibit tumor growth and migration.At present,VEGFR-2 has become an important target in the research of tumor angiogenesis drugs.Its inhibitors are mainly heterocyclic structure,which can combine with ATP active cavity to inhibit kinase activity,and indole structure is an important parent nucleus.In addition,benzimidazole/benzothiazole compounds have a wide range of biological activities and broad prospects in drug research and development.In this paper,by using the method of CADD and active splicing principle,we combine indole structure and benzoheterocycle structure through different acyl bond,and design two kinds of leading compounds of VEGFR-2 inhibitors,in order to explore the best way of combination,and lay a good foundation for the development of new antitumor drugs.The main contents of the study are as follows:1.Indole-3-acetic acid and indole-3-propionic acid intermediates with different substituents were synthesized by Huang Minglong reduction reaction,Fischer cyclization reaction and Michael addition reaction,and the synthesis process was optimized.2.Synthesis of 2-substituted benzimidazole derivatives by nucleophilic substitution and dehydration.3.The target compounds of indole benzothiazoles were synthesized by esterification or acylation of indole carboxylic acid derivatives with 2-substituted benzimidazoles or benzothiazoles,including indole benzothiazoles and indole benzothiazolamide.4.The inhibitory activities of some of the target compounds on A549 and HeLa cells were determined,and their docking with VEGFR-2 was studied.In this study,24new indole carboxylic acid benzo heterocyclic derivatives were synthesized.It was found that indole benzimidazoles and indole benzothiazolamide target compounds have certain antitumor activity and VEGFR-2 binding ability,among which 1h and 1j have strong antitumor activity,with IC₅₀ up to 40?M/mL,while 1h,2b,3a,3b and 6a have strong VEGFR-2 binding ability.When the number of carbon atoms is more than three,and benzo heterocycle is connected with hydrophobic group,the configuration of the compound is the optimal,meanwhile,the docking energy is the lowest.It was found for the first time that the binding mode of indole and benzo heterocyclic structure with VEGFR-2 active cavity was different,and the binding ability was different with the length of the binding bond.The results show that indole benzo heterocycles have a strong potential for the development of tumor drugs.This study provides a new way to explore the improvement of heterocyclic VEGFR-2 inhibitors and is of great significance for the development of new anti-tumor drugs.