Department of Woman's and Child's Health, Hemato-Oncology Lab, University of Padova, 35128 Padova, Italy.
Laboratory of Experimental Pharmacology, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, 35128 Padova, Italy.
Int J Mol Sci. 2024 Jul 9;25(14):7519. doi: 10.3390/ijms25147519.
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 -hydroxyacrylamide or a -hydroxypropiolamide at the 5-position of the 2-aroylbenzo[]furan skeleton, to produce compounds - and -, respectively. Among the synthesized compounds, derivatives , , , , and showed excellent antiproliferative activity, with IC 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 and 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 -, , , , and , although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.
由于微管蛋白和组蛋白去乙酰化酶抑制剂之间存在协同作用，我们使用药效团融合策略来生成潜在的微管蛋白-HDAC 双重抑制剂。药物设计基于在 2-芳酰基苯并呋喃骨架的 5-位引入 -羟基丙烯酰胺或 -羟基丙稀酰胺，分别产生化合物 - 和 -。在所合成的化合物中，衍生物 、 、 、 、 和 对 A549、HT-29 和 MCF-7 细胞具有优异的抗增殖活性，对单或双位数纳摩尔级别的细胞 IC 值具有抑制作用，对对照化合物 combretastatin A-4（CA-4）具有抗性。化合物 、 和对 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 的抑制活性时，我们发现 、 、 、 和 ，尽管作为微管蛋白组装的抑制剂非常有效，但对 HDAC6 没有显著的抑制活性。
