Bionomics Ltd., 31 Dalgleish Street, Thebarton, South Australia, 5031, Australia.
J Med Chem. 2011 Sep 8;54(17):6014-27. doi: 10.1021/jm200454y. Epub 2011 Aug 5.
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).
通过对新型微管聚合抑制剂的构效关系（SAR）进行指导设计，得到了一系列苯并[b]呋喃类化合物，它们对癌细胞和激活的内皮细胞具有优异的活性。通过在药效团中引入构象偏差和额外的氢键供体，早期先导化合物的活性得到了显著提高。对一系列具有高聚合抑制剂活性的化合物进行了针对癌细胞和激活的内皮细胞与静止的内皮细胞的选择性筛选，得到了 7-羟基-6-甲氧基-2-甲基-3-(3,4,5-三甲氧基苯甲酰基)苯并[b]呋喃（BNC105，8）作为一种有效的选择性增殖抑制剂。由于溶解度差，8 被作为其二钠盐前药 9（BNC105P）给药，在体内迅速被裂解为活性 8。与基准药物 combretastatin A-4 二钠盐 5（CA4P）相比，9 表现出更好的血管破坏和肿瘤生长抑制作用。
