Design, Synthesis And Anti-tumor Activity Of Two Types Of Colchicine Binding Site Inhibitors

Colchicine binding site inhibitors(CBSIs)have attracted considerable attention in recent years,due chiefly to their dual proliferation-inhibiting/vascular-disrupting activities,resulting in more than 30 drug candidates currently under clinical trials.Most CBSIs possess small molecular weight with chemically modifiable structures,thus they afford adequate space for chemical modification to improve efficacy,pharmacokinetic properties and reduce toxicity.Combretastatin A-4(CA-4)and its analogues,as one family of CBSIs,have attracted much interest as a lead compound in the development of new anticancer agents due to the strong potency and the relatively simple structure.The structual features and structure-activity relationships(SARs)of CA-4 analogues have been summarized in this thesis.On this basis,three series of novel CA-4 analogues,including 3-(3,4,5-trimethoxybenzoyl)quinoxaline derivatives,5-aryl-3-(3,4,5-trimeth-oxybenzoyl)-1,2,4-oxadiazoles derivatives and 2-aryl-4-alkyl-5-(3,4,5-trimethoxybenzyl)imidazoles derivatives,were design via the fragment-based approach.All of these target compounds were synthesized and evaluated for their in vitro antiproliferative activities against three human carcinoma cell lines(SGC-7901 cells,A549 cells and HT-1080 cells)using a standard MTT assay.Most compounds exhibited moderate to strong antiproliferative activity.The representative compounds GQ1-2a and GQ2-2b were selected to investigate the antitumor mechanisms.The results indicated that they significantly induced cell cycle arrest in the G2/M phase and caused microtubule destabilization.JG-03-14,a new scaffold CBSIs,has a broad spectrum of anticancer activity.To extend our knowledge of the imidazole or the 1,3-selenazole as a bioisostere for the pyrrole present in JG-03-14,two series of novel JG-03-14 analogues,such as 2-(3,4-dimethoxyphenyl)-4-methyl-1H-imidazole-5-carboxylic acid ethyl ester derivatives and 2-(4-alkoxy-3-nitrophenyl)-4-methyl-1,3-selenazole-5-carboxylic acid ethyl ester derivatives,were designed.All of the target compounds were synthesized and evaluated for their in vitro antiproliferative activities.Unfortunately,these compounds showed no significant effects.This result indicated that the substituted pyrrole is essential for activity.It was noted that 2-(4-alkoxy-3-nitrophenyl)-4-methyl-1,3-selenazole-5-carboxylic acids might be a set of potential xanthine oxidase inhibitors(XOI)via similarity-based virtual screening.The data of bioassay in vitro showed that they possessed potent inhibitory activity against XO.Among them,GQ5-2e emerged as the most potent XOI(IC50=16.1 nM)in comparison to febuxostat(IC50=18.6 nM).In addition,the structure-activity relationship analyses have also been presented to provide a basis for the further structure-guided design of novel CBSIs and XOIs.