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Discovery and investigation of antiproliferative and apoptosis-inducing properties of new heterocyclic podophyllotoxin analogues accessible by a one-step multicomponent synthesis.

Authors
Type
Published Article
Journal
Journal of medicinal chemistry
Publication Date
Volume
50
Issue
21
Pages
5183–5192
Identifiers
PMID: 17894480
Source
Medline
License
Unknown

Abstract

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

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