Anticancer Properties of an Important Drug Lead Podophyllotoxin Can Be Efficiently Mimicked by Diverse Heterocyclic Scaffolds Accessible via One-Step Synthesis

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• 作者：Igor V. Magedov ; Liliya Frolova ; Madhuri Manpadi ; Uma devi Bhoga ; Hong Tang ; Nikolai M. Evdokimov ; Olivia George ; Kathy Hadje Georgiou ; Steffen Renner ; Mattha虉us Getlik ; Tiffany L. Kinnibrugh ; Manuel A. Fernandes ; Severine Van slambrouck ; Wim F. A. Steelant ; Charles B. Shuster ; Snezna Rogelj ; Willem A. L. van Otterlo ; Alexander Kornienko
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4234-4246
• 全文大小：1181K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

Structural simplification of an antimitotic natural product podophyllotoxin with mimetic heterocyclic scaffolds constructed using multicomponent reactions led to the identification of compounds exhibiting low nanomolar antiproliferative and apoptosis-inducing properties. The most potent compounds were found in the dihydropyridopyrazole, dihydropyridonaphthalene, dihydropyridoindole, and dihydropyridopyrimidine scaffold series. Biochemical mechanistic studies performed with dihydropyridopyrazole compounds showed that these heterocycles inhibit in vitro tubulin polymerization and disrupt the formation of mitotic spindles in dividing cells at low nanomolar concentrations, in a manner similar to podophyllotoxin itself. Separation of a racemic dihydropyridonaphthalene into individual enantiomers demonstrated that only the optical antipode matching the absolute configuration of podophyllotoxin possessed potent anticancer activity. Computer modeling, performed using the podophyllotoxin binding site on 尾-tubulin, provided a theoretical understanding of these successful experimental findings.