Discovery and Investigation of Antiproliferative and Apoptosis-Inducing Properties of New Heterocyclic Podophyllotoxin Analogues Accessible by a One-Step Multicomponent Synthesis

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• 作者：Igor V. Magedov ; Madhuri Manpadi ; Severine Van slambrouck ; Wim F. A. Steelant ; Elena Rozhkova ; Nikolai M. Przheval'skii ; Snezna Rogelj ; Alexander Kornienko
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：October 18, 2007
• 年：2007
• 卷：50
• 期：21
• 页码：5183 - 5192
• 全文大小：445K
• 年卷期：v.50,no.21(October 18, 2007)
• ISSN：1520-4804

文摘

Podophyllotoxin has been extensively used as a lead agent in the development of new anticancer drugs. Onthe basis of the previously reported simplified 4-aza-2,3-didehydro podophyllotoxin analogues, weimplemented a bioisosteric replacement of the methylenedioxybenzene subunit with a pyrazole moiety toafford tetracyclic dihydropyridopyrazoles. Libraries of these structurally simple analogues are prepared bya straightforward one-step multicomponent synthesis and demonstrated to display antiproliferative propertiesin a number of human cancer cell lines. These new heterocycles potently induce apoptosis in cancerousJurkat cells even after a short 24 h exposure. In contrast, no apoptosis is detected in primary lymphocytesunder the same treatment conditions. The ease of synthesis and encouraging biological activities make thepresented library of dihydropyridopyrazoles promising new leads in anticancer drug design.