| Summary: | 碩士 === 臺北醫學大學 === 藥學研究所 === 96 === Two novel series of 7-anilino-6-azaindole-1-sulfonamides and 7-aryl-6- azaindole-1-sulfonamides based on N-[2-[(4-hydroxyphenyl) amino]-3- pyridinyl]-4-methoxybenzenesulfonamide (ABT-751) as a template were synthesized as potent antiproliferative agents. ABT-751 is an orally-active anticancer agent acting through the binding with the colchicine binding site on the tubulin. It is now undergoing human clinical trial. Based on the more potent antiproliferative activity of 7-aryl-6-azaindole-1-sulfonamides, another two novel series of 7- arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamides were synthesized. The synthesis of 7-aryl-6-azaindole-1-sulfonamide derivatives started from 2-bromo-3-nitropyridine, which was subjected to the vinyl magnesium bromide to give 7-bromo-6-azaindole, treated with 4-methoxybenzenesulfonyl chloride to afford the 6-azaindole -1-sulfonamides. A Suzuki reaction at 7-position, utilizing the 7-bromo -6-azaindole was treated with a variety of phenylboric acid to give the designed 7-aryl substituted 6-azaindoles. 7-arylindole-1-sulfonamides and 7-arylindoline-1-sulfonamide derivatives were prepared started from 1-bromo-2- nitrobenzene by the same procedure. Three types of core structure analogous, for example, 7-aryl-6-azaindoles (20-24), 7-arylindoles (18-19) and 7-arylindolines (1-17) were evaluated their antiproliferative activity against oral epidermoid carcinoma KB cells. In the preliminary data, compounds 1, 2, 4, 5, 9, 11, 12, 14, 15, 23, and 24 demonstrate substantial activity with IC50 values ranging from 15-50 nM. Structure- activity relationship information revealed that 7-aryl-6- azaindole-1- sulfonamide and 7-arylindoline-1-sulfonamide derivatives were more potent than 7-arylindole-1-sulfonamide derivatives. These findings have encouraged us to extensively explore these two novel sulfonamides and further investigate their mode of actions and mechanisms.
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