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Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors.

ABSTRACT: Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KB(VIN), and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41 ?M in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC(50) 1.4-1.7 ?M) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity.

SUBMITTER: Wang XF 

PROVIDER: S-EPMC3546147 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors.

Wang Xiao-Feng XF   Ohkoshi Emika E   Wang Sheng-Biao SB   Hamel Ernest E   Bastow Kenneth F KF   Morris-Natschke Susan L SL   Lee Kuo-Hsiung KH   Xie Lan L  

Bioorganic & medicinal chemistry 20121206 3

Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KB(VIN), and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41 μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC(50) 1.4-1.7 μM) and competitively inhibited colchicine binding  ...[more]

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