Design,synthesis And Antitumor Activity Evaluation Of Novel Sulfonamide Microtubule Inhibitors

Microtubules are important components in eukaryotic cells,which participate in various basic processes of cells,including the formation of spindles in the process of mitosis especially and the separation of chromosomes by their own dynamic properties.It has been found that inhibiting polymerization or depolymerization of microtubules can effectively inhibit tumors.Among the four main microtubule targets,drugs targeting colchicine site have the advantages of relatively high water solubility to multi-drug resistant tumor cells,and there is still no antitumor drug on the market targeting the colchicine site,so the research and development prospect are broad.Sulfonamide is an important chemical scaffold with a simple structure.,which can easily introduce different substituent groups and show different biological activities.At present,many drugs contain sulfonamide groups in the structure,showed good biological activity,such as antibacterial,antiviral,antitumor and so on.Sulfonamides as the basic backbone are often designed as microtubulin inhibitors,acting at the colchicine binding site to inhibit microtubulin polymerization and exert antitumor activity,with good inhibitory activity against a variety of tumor cells including multidrug-resistant tumor cells.In this thesis,we used sulfonamide as the basic backbone,and used the principle of molecular splicing principle to splice the antitumor active fragments of 3,4,5-trimethoxyphenyl,piperazine and aminodithio into one molecule to obtain two series of novel tertiary sulfonamides,and evaluated the antitumor activity in vitro of the synthesized compounds,and selected the two compounds with the best antitumor activity in vitro,A15 and C5,for validation of microtubulin inhibitory activity.The specific work is as follow:1.Based on the previous work of our research group,novel tertiary sulfonamide derivatives,the seriesⅠ,were obtained by structural optimization of compound 6,a microtubule polymerization inhibitor,with a total of 27 derivatives.Considering the antitumor activity and modification difficulty and other factors,compound A19 was selected as the lead compound to synthesize series II new aminodithio-sulfonamide derivatives,a total of 18 compounds.2.The anti-proliferative activity of 45 compounds against human gastric cancer cells MGC-803,human colon cancer cells HCT-116 and human esophageal squamous cells KYSE-450 in vitro was evaluated by the thiazolyl blue（MTT）method.According to the results of the antitumor activity of the compound,a preliminary structure-activity relationship analysis was performed.The experimental results showed that compounds A4 and A15 in series I showed the best anti-proliferative activity and the IC₅₀ values against MGC-803,HCT-116 and KYSE-450 were 62 n M,51 n M,82 n M and 45 n M,82 n M,66 n M,respectively,which were better than the positive control drug colchicine.The most of compounds in Series II showed good antitumor activities against these three types of tumor cells,and the compound C5 was the best one.Compound C5showed selective inhibition on MGC-803 with the IC₅₀ value of 21 n M.3.Compounds A15 and C5,the most active compounds in seriesⅠandⅡ,were selected for tubulin evaluation in vitro.The result showed that compounds A15 and C5could effectively inhibit tubulin polymerization in a concentration-dependent manner.At the concentration of 3μM/L,the inhibitory activity of compound A15 inhibited microtubule polymerization better than the positive control drug Colchicine.At the concentration of 10μM/L,the activities of compounds A15 and C5 were similar.4.Compound A15,which has better inhibitory activity against microtubule polymerization,was selected to simulate its binding with colchicine site ofβ-tubule protein（PDB ID:1SA0）by MOE software（2015.10）.The result showed that compound A15 formed intermolecular hydrogen bonds with the main chains of valine-236 and leucine-246 at the colchicine site ofβ-tubulin,and had hydrophobic effect with the surrounding amino acid residues,resulting in tighter binding,which were the important reasons for its excellent microtubulin polymerization inhibition activity and antitumor activity.