Design,Synthesis And Biological Evaluation Of Novel Chalcone Tubulin Polymerization Inhibitors

Microtubules play an important role in the life cycle of the cell,which are involved in a series of cellular processes such as cell division and cell proliferation,and have been considered as a major target for the development of novel anticancer agents in recent years.The clinical using of tubulin polymerization inhibitors existed was always limited by complex synthesis,low oral bioavailability,drug resistance and side effects.Therefore,it is imperative for pharmacy workers to search and synthesize high effective and low toxicity of microtubulin drugs.Chalcones have extensive bioactivities,including antiallergic,anti-inflammatory and anticancer activities.It's antitumor activity has always been the concern of pharmacy workers.The study found that we can modify and transform chalcone derivatives'structure in an effort to further improve its antiproliferative activity,such as introducing different substituents on the benzene-ring.This also makes it possible to design and synthesize new chalcone tubulin polymerization inhibitors.In this paper,Twenty-four chalcone derivatives were designed and synthesized including 7a-7l and12a-12l.Structures of target molecules were confirmed by ¹H NMR,¹³C NMR and HR-MS and not reported previously.The in vitro inhibitory effect of twenty-four chalcones derivatives were evaluated against HepG-2,NCI-H460,MGC-803,SK-OV-3,T-24,HL-7702 normal cells line.The results showed that all of the compounds exhibited good cytotoxicity and had low cytoxicity on normal human cell line?HL-7702?(IC₅₀>50?M)except for compound12g.According to the analysis of constitutive relationship,the presence of a electron-donating moiety in position C-2 and C-4 of the benzene group seemed to be associated with a general increase in activity within compounds 7a-7l,such as 7b,7c,7h and 7i,compared with other analogues substituted by halogen,such as 7a,7d-7g and 7j-7l.It was important to note that compounds 12j-12l which was with a halogen substituent in the C-2 position of the benzene ring,showed reverse effects as compared with 7j-7l.Moreover,the modifications of 4-position of phenyl ring with halogen or hydroxy moiety caused a loss of potency,such as 12d-12g.Among all target compounds,it was notable that compound 12k exhibited the best antitumor activity with IC₅₀ values ranging from 3.75 to 8.42?M,which was better than Millepachine with IC₅₀ values ranging from 4.54 to 11.05?M.What's more,the activity of compound 12k was not markedly vary for two paclitaxel-resistant cancer cells compared with the sensitive ones.Related mechanism of representative compound 12k was conducted by Molecular Docking,Cell cycle and Western Blotting.Then we found that the compounds tested could induced apoptosis through endogenous pathway.The intracellular compound 12k could disrupt the normal function of tubulin by binding to tubulin,and arrested the cells at the G2/M phase.A large number of reactive oxygen species was produced when the cancer cell was under stress,then by the regulation of apoptosis-related proteins,such as Bax/Bcl-2,and the apoptosis was induced finally.