Synthesis And In Vitro Anti-tumor Activity Of Bicyclic Clarithromycin Derivatives And 2,3-diarylthiophene Compounds

Erythromycin has been widely used in the treatment of bacterial infections.In addition to the anti-microbial effect,Erythromycin and its derivatives showed some other activities,such as gastrointestinal contractile activity,anti-inflammatory activity,luteinizing hormone-releasing hormone antagonistic activity and phosphodiesterase-3 inhibitory activity.Moreover,they had beneficial effect on the treatment of tumor.In this paper,We have synthesized two series of derivatives based on 8,9,10,11-Dianhydro-clarithromycin 9,12-Hemiketa which had anti-proliferative activity,3-cladinosly-8,9;10,11-Dianhydro-N-demethyl-clarithromycin derivatives and 3-carboxide-8,9;10,1 1-Dianhydro-N-demethyl-clarithromycin derivatives.We used Pfitzner-Moffatt reaction to realize the oxidation of 3-OH.All compounds’ chemical structures were characterized by the applications of 1H-NMR,13C-NMR and MS.The data of 13C-NMR spectra were discussed briefly.New compounds had been evaluated for their anti-proliferative activities against human SGC-7901,KB and HT-1080 cell lines by MTT assay.The activities of WZ-02,WZ-07 and WZ-13 were best,with IC50 of 1.0-10.0 μM for three cell lines.Combretastatin A-4(CA-4),naturally occurring stilbenes,was isolated from Combretum caffrum by Pettit group.This substance strongly inhibited the polymerization of tubulin by binding to the chochicine site and was one of the most potent antivascular and antimitotic agents.Thiophene are structural units of many natural and biologically interesting compounds which can be considered as an important pharmacophore moiety.In the present study,we designed and synthesized a new series of 2,3-diarylthiophene analogues of Combretastatin A-4 based on the preliminary works of our group.In this study,two different 1,2-diarylethanone were respectively prepared from the starting 3,4,5-trimethoxybenzaldehyde by two simple "one pot" reactions,which were then converted to the corresponding ethyl 4,5-diarylthiophene-2-carboxylate derivatives by Vilsmeier-Haack reaction and cyclization reaction.Treatment of the ethyl 4,5-diarylthiophene-2-carboxylate with NaOH under reflux resulted in the corresponding 4,5-diarylthiophene-2-carboxylic acid derivatives which were then reacted with Cu2O to yield desired 2,3-diarylthiophene derivatives.The structures of these compounds were confirmed by detailed NMR/MS analysis.The anti-proliferative activities of the target compounds were evaluated by MTT assay in vitro against SGC-7901,HT-1080 and KB cell lines.Among these compounds,A-3-5 exhibited superior potency against different tumour cell lines.Moreover,it significantly inhibited tubulin polymerisation into microtubules and caused microtubule destabilisation.In addition,a molecular modelling study of A-3-5 was performed to clarify its binding mode at the colchicine site in the tubulin dimer and to provide a basis for further structure-guided design of novel CA-4 analogues.