Discovery of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a Tubulin Polymerization Inhibitor with Potent Antiproliferative and Tumor Vascular Disrupting Prope

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• 作者：Bernard L. Flynn ; Gurmit S. Gill ; Damian W. Grobelny ; Jason H. Chaplin ; Dharam Paul ; Annabell F. Leske ; Tina C. Lavranos ; David K. Chalmers ; Susan A. Charman ; Edmund Kostewicz ; David M. Shackleford ; Julia Morizzi ; Ernest Hamel ; M. Katherine Jung ; Gabriel Kremmidiotis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：September 8, 2011
• 年：2011
• 卷：54
• 期：17
• 页码：6014-6027
• 全文大小：1247K
• 年卷期：v.54,no.17(September 8, 2011)
• ISSN：1520-4804

文摘

A structure鈥揳ctivity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).