PDF(Pubmed)
Abstract：
Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.
摘要：
由于微管蛋白和HDAC抑制剂之间的协同作用，我们使用药效团融合策略来产生潜在的微管蛋白-HDAC双重抑制剂.药物设计基于在2-芳基苯并[b]呋喃骨架的5位引入N-羟基丙烯酰胺或N-羟基丙酰胺，为了产生化合物6a-i和11a-h，分别。在合成的化合物中，导数6a，6c,6e,6g,11a,11c表现出优异的抗增殖活性，IC50值在一位数或两位数纳摩尔水平，抗A549、HT-29和MCF-7细胞对对照化合物康布他汀A-4(CA-4)具有抗性。化合物11a和6g对Hela细胞系的活性也比CA-4高10倍。当比较微管蛋白聚合的抑制作用与HDAC6抑制活性时，我们发现6a-g,6i,11a,11c,11e，虽然作为微管蛋白组装的抑制剂非常有效，对HDAC6没有显著的抑制活性。
