Structural simplification of bioactive natural products with multicomponent synthesis. 2. Antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones

Igor V. Magedov, Madhuri Manpadi, Marcia A. Ogasawara, Adriana S. Dhawan, Snezna Rogelj, Severine Van Slambrouck, Wim F.A. Steelant, Nikolai M. Evdokimov, Pavel Y. Uglinskii, Ecrik M. Elias, Erica J. Knee, Paul Tongwa, Mikhail Yu Antipin, Alexander Kornienko

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Abstract

Pyrano[3,2-c]pyridone and pyrano[3,2-c]quinolone structural motifs are commonly found in alkaloids manifesting diverse biological activities. As part of a program aimed at structural simplification of bioactive natural products utilizing multicomponent synthetic processes, we developed compound libraries based on these privileged heterocyclic scaffolds. The selected library members display low nanomolar antiproliferative activity and induce apoptosis in human cancer cell lines. Mechanistic studies reveal that these compounds induce cell cycle arrest in the G2/M phase and block in vitro tubulin polymerization. Because of the successful clinical use of microtubule-targeting agents, these heterocyclic libraries are expected to provide promising new leads in anticancer drug design.

Original languageEnglish (US)
Pages (from-to)2561-2570
Number of pages10
JournalJournal of medicinal chemistry
Volume51
Issue number8
DOIs
StatePublished - Apr 24 2008
Externally publishedYes

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