Synthesis And Bioactive Evaluation Of Compounds Containing Sulfonamide And Oxime Skeleton

Part ⅠSulfonamide drugs were used in clinical antibacterial field initially, however, some were developed as anti-inflammatory, anti-viral, anti-tumor agents and part of them had been used in clinical treatment. In this part, we have designed and synthesized several series of novel compounds containing sulfonamide skeleton, then finished activity screening and structure-activity relationship studies. Many of these compounds exhibited good anticancer and enzyme inhibitory effects. According to the principle of structure-based design, we have totally designed and synthesized70compounds (59of them were firstly reported) by means of molecular simulation technology. Finally, we have tested their biological activities, which were summarized below.(1) We synthesized a series of novel tubulin polymerization inhibitors (2-22to2-61) containing cinnamyl skeleton and sulfonamide skeleton, and tested their biological activity. These compounds exhibited potential inhibitory activity against tubulin polymerization and anti-proliferative activity against mouse melanoma cells. Compounds2-29exhibited the best inhibitory activity on tubulin and cancer cell with IC50values of2.4μg/mL and0.8μg/mL. In order to further investigate the mode of action between them, we performed molecular simulation. The result showed that there were few interactions between the amino acid residues in the colchicine action sites of tubulin with the compound, which might play an important role in the activity.(2) In this section, we synthesized a series of novel EGFR inhibitors (3-11to3-15and3-21to3-45) containing nitroimidazole skeleton (or substituted phenylacetyl skeleton) and benzenesulfonamide skeleton, and tested their biological activity. These compounds exhibited potential inhibitory activity against EGFR and HER-2, meanwhile showed good antiproliferative activity against lung cancer cells and mouse melanoma cells. Compound3-13showed the best inhibitory activity against EGFR and cancer cells. The molecular simulation results showed that there were a few interactions between compounds and the amino acid residues in the ATP binding site of EGFR.Part ⅡSimilarly, due to the various biological activities, oxime derivatives have also become a hot area of research. In this part, we have focused on oxime derivatives. We have designed and synthesized several series of novel compounds containing the oxime skeleton, then finished activity screening and structure-activity relationship studies. Many of these compounds exhibited good antimicrobial or immunosuppressive effects. According to the principle of structure-based design, we have totally designed and synthesized52compounds (47of them were firstly reported) by means of molecular simulation technology. Finally, we have tested their biological activities, which were summarized below.(3) In this section, s series of novel deoxybenzoin derivatives (5-31-5-40) were synthesized and their immunosuppressive activities were tested. Most of the deoxybenzoin oxime derivatives exhibited good immunosuppressive activities. Compound5-31showed the best activity with SI>684.64, better than reference drug CsA (SI=235.44). In general, electron-donating groups in the position R2and R3could improve the immunosuppressive activity. In cytotoxicity assay, compounds5-31did not show significant toxicity on normal lymph node cells. In addition, Western blot analysis results showed that the immune suppression process was promoted by apoptosis of lymph node cells with the involvement of caspase-3and PARP. All results revealed the enormous potential of these compounds in the future development of new immunosuppressive agents.(4) Based on the previous results, we designed and synthesized a series of novel chalcone oxime derivatives (6-23-6-44) and test their immunosuppressive activities and cytotoxicities. Most chalcone oximes showed good activity and compounds6-27showed the best activity with SI=176.69, better than the reference drug CsA (SI=154.13). SAR analysis result showed that the electronegativity of the substituents on the two benzene rings of the compound influenced compounds’ activity. Further in vitro pharmacological experiments showed that immunosuppressive activity of the compound was achieved by promoting the apoptosis of lymph node cells and enhancing cleavage level of caspase-3and PARP.