Design, Synthesis And Bioactive Evaluation Of Pyridine Acyl-sulfonamide Derivatives And Novel Chalcone Derivatives

With the development of science and technology, the study of anticancer drugs has entered a new stage. New anticancer drugs acting on molecular targets begin to be excavated. In recent years, the domestic and international researches find that cyclooxygenase-2 (COX-2) is closely related breast tumorigenesis. COX-2 is involved in the progression and metastasis of cancer cells and has gradually become a new target for anti-cancer drugs. In addition, a powerful anti-cancer drugs target tubulin has been a research focus because of its important role in mitosis. This thesis is to study these two targets inhibitors. We synthesized two series of compounds and evaluated their biological activity. It was desirable to have good inhibitory compounds were screened for each target.Based on the study that celecoxib containing benzene sulfonamide structure as COX-2 inhibitors can inhibit cancer cell proliferation, we designed a series of acyl sulfonamide derivatives (1-24). Certainly, the structure identify of all compounds were also performed, including H NMR, ESI-MS, elemental analysis and crystal structure determination. Then, biological activity of this series of compounds were measured, including anti-HepG2, anti-MCF-7, anti-B16-F10 proliferation assay, COX-1 and COX-2 inhibition assay and western tests. Given the combination of molecular modeling and biological activity screening results, we found that most of the synthesized compounds were proved to be potent and selective inhibitors of COX-2. Especially, compound 23 showed best COX-2 inhibition activity, with IC50 value of 0.8μM. All of compounds showed broad-spectrum antitumor activity with IC50 concentration range of 1.2-20.2μM against the three cancer cell lines mentioned above. Compound 23 showed the best anti-proliferative activity of B16-F10, MCF-7 and HepG2 (IC50= 0.8,1.8 and 0.2μM). In addition, the small-molecule docking simulations were performed to give the probable binding modes of these compounds into the COX-2 active binding site of COX-2, which would give the support to these results. Western blotting assay further confirmed that compound 23 with the concentration above 0.75μM could obviously inhibit lipopolysaccharide (LPS)-induced COX-2 expression in murine macrophage RAW264.7 cell line. Therefore, compound 23 may be useful as a lead compound for superior COX-2 inhibitors.After many years of research, some compounds of tubulin inhibitors which have been synthesized exhibit a strong anti-tumor activity. Combretastatin A-4 (CA4), Combretastatin A4 phosphate (CA4P) and Combretastatin A-4 analogs become a current research focus in recent years, and achieved very great development. We found all of these compounds had the chalcone skeleton structure. In order to obtain better anti-tubulin polymerization and more effective compounds to inhibit tumor cell proliferation, we take some structural modifications and transformations for chalcone skeleton.Herein, a novel series of chalcone derivatives(1-20) were synthesized. All of them were new and were not reported on antitumor activity. The anti-proliferation as well as the enzyme inhibitory experiments suggested that most of them were potent. Compound 4 displayed the most potent activity against tubulin (IC50= 1.42μg/mL), being comparable with the positive control Colchicine (IC50= 0.81μg/mL) and CA-4 (IC50= 1.70μg/mL). Compound 4 displayed the most potent activity against MCF-7 cell line (IC50= 0.03μg/mL). The docking simulation was performed to analyze the probable binding models. Furthermore, compound 4 was further assayed for its effect on cell cycle using flow cytometry.67.93% of these cells were arrested at G2/M.These findings indicate a continuing impairment of cell division and confirm compound 4 is a potent antitubulin agent.