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 properties.
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| Abstract |
A structure-activity 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).
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| Authors | 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 |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 17 Pg. 6014-27 (Sep 08 2011) ISSN: 1520-4804 [Electronic] United States |
| PMID | 21774499 (Publication Type: Journal Article) |
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