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
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
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DOI：
10.1021/jm701499n
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发表时间：
2008-04-24
影响因子：
7.3
通讯作者：
Kornienko, Alexander
中科院分区：
文献类型：
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作者：
Magedov, Igor V.;Manpadi, Madhuri;Kornienko, Alexander
吡喃并[3，2-c]吡啶酮和吡喃并[3，2-c]喹诺酮结构基序是生物碱中常见的结构基序，具有多种生物活性。作为旨在利用多组分合成工艺简化生物活性天然产物结构的计划的一部分，我们开发了基于这些特权杂环支架的化合物库。所选择的文库成员在人癌细胞系中显示低纳摩尔抗增殖活性并诱导凋亡。机制研究表明，这些化合物诱导细胞周期停滞在G2/M期，并在体外阻断微管蛋白聚合。由于微管靶向药物的成功临床应用，这些杂环库有望为抗癌药物设计提供有前途的新线索。
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.