The Design,Synthesis,in Vitro Biological Evaluation And Molecular Modeling Of Novel Benzenesulfonate Derivatives Bearing Chalcone Moieties As Potent Anti-microtubulin Polymerization Agents

Compounds bearing chalcone moiety were proved with broad-spectrum anti-bacteria activity,anti-tumor activity and anti-inflammatory activity,hence,chalcones raise increasing focuses in drug discovery as well as it is intensely emphasized organic chemically.When it comes to the studies regarding mechanism of compounds bearing chalcone moiety,the way it works upon angiogenesis and mitosis,gives it a mountain of attentions and great in-depth researches.Meanwhile,benzenesulfonates also play significant roles in anti-tumor drugs’ research,for its exceptionally vivid chemical characteristics and various biological activities.This thesis covers a modification onto the chemical structures of Colchicine and CA-4,with the insertion of chalcone skeleton and a benzenesulfonate moiety.With the favor from CADD,we designed,synthesized a novel series of benzenesulfonates analogues bearing chalcone moiety as microtubulin polymerization inhibitors.From the outcomes of original biological screening and SARs study,most compounds of the series demonstrated proliferative inhibiting functions against several carcinoma cell lines at nmol level,as well as microtubulin inhibitory activities.The specific study includes:A.CDOCKER protocol in Discovery Studio 3.5 was used to process crystal of microtubules(PDB code 1SAO).The modified microtubule crystal(receptor)then was run docking calculation with ligands(small molecules designed as targeting candidates)in the defined active site.Compare the interaction energies,intermolecular forces of ligands with those of colchicine(positive control),19 compounds were chosen from.B.First a series of chalcones 1a-19a were synthesized as in pre-described methodologies,3,4-dimethoxybenzene-l-sulfonyl chloride then reacted with la-19a as in sulfonation reaction,obtaining 19 final products.The structures of 19 compounds 1b-19b were identified with analytical protocols like 1H NMR,13C NMR,MS,single crystallographic diffraction.C.Biological assays contain two steps in general.First,screen proliferative inhibitory activities of 1b-19b against several carcinoma cell lines obtaining IC50 values and CC50 values against normal cell line 293T,respectively.Among the 19 compounds,compound 10bpresents a relatively strong inhibitory activity against MCF-7 cell line(IC50 79.2 nM,while Colchicine’s IC50 value is 150.4 nM,nearly 2 times of 10b’s),then 10bwas selected to perform microtubulin inhibitory activity(IC50 12.0 μM)whenCA-4 as positive control(IC50 value is 3.4 μM).Second,compound 10b was tested flow cytometry to study its effects on apoptosis,cell cycle,DAPI fluorescent staining was also used to give observation of how 10b causes apoptosis of MCF-7 cells visually.