Barbosa Gisele, Gelves Luis Gabriel Valdivieso, Costa Caroline Marques Xavier, Franco Lucas Silva, Lima João Alberto Lins de, Aparecida-Silva Cristiane, Teixeira John Douglas, Mermelstein Claudia Dos Santos, Barreiro Eliezer J, Lima Lidia Moreira
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
Programa de Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
Pharmaceuticals (Basel). 2022 Jul 23;15(8):913. doi: 10.3390/ph15080913.
Combretastatin A-4 (CA-4, ) is an antimicrotubule agent used as a prototype for the design of several synthetic analogues with anti-tubulin activity, such as LASSBio-1586 (). A series of branched and unbranched homologs of the lead-compound and vinyl, ethinyl and benzyl analogues, were designed and synthesized. A comparison between the cytotoxic effect of these homologs and on different human tumor cell lines was performed from a cell viability study using MTT with 48 h and 72 h incubations. In general, the compounds were less potent than CA-4, showing CC values ranging from 0.030 μM to 7.53 μM (MTT at 72 h) and 0.096 μM to 8.768 μM (MTT at 48 h). The antimitotic effect of the target compounds was demonstrated by cell cycle analysis through flow cytometry, and the cellular mechanism of cytotoxicity was determined by immunofluorescence. While the benzyl homolog (LASSBio-2070) was shown to be a microtubule stabilizer, the lead-compound (LASSBio-1586) and the methylated homolog (LASSBio-1735) had microtubule destabilizing behavior. Molecular docking studies were performed on tubulin protein to investigate their binding mode on colchicine and taxane domain. Surprisingly, the benzyl homolog was able to modulate EGFR phosphorylate activity in a phenotypic model. These data suggest LASSBio-2070 () as a putative dual inhibitor of tubulin and EGFR. Its binding mode with EGFR was determined by molecular docking and may be useful in lead-optimization initiatives.
康普瑞他汀A-4（CA-4）是一种抗微管剂，用作设计几种具有抗微管蛋白活性的合成类似物的原型，如LASSBio-1586。设计并合成了一系列先导化合物的支链和直链同系物以及乙烯基、乙炔基和苄基类似物。通过使用MTT进行48小时和72小时孵育的细胞活力研究，对这些同系物和[具体化合物]对不同人类肿瘤细胞系的细胞毒性作用进行了比较。总体而言，这些化合物的效力低于CA-4，其CC值范围为0.030 μM至7.53 μM（MTT 72小时）和0.096 μM至8.768 μM（MTT 48小时）。通过流式细胞术进行细胞周期分析证明了目标化合物的抗有丝分裂作用，并通过免疫荧光确定了细胞毒性的细胞机制。虽然苄基同系物（LASSBio-2070）被证明是一种微管稳定剂，但先导化合物（LASSBio-1586）和甲基化同系物（LASSBio-1735）具有微管去稳定行为。对微管蛋白进行了分子对接研究，以研究它们在秋水仙碱和紫杉烷结构域上的结合模式。令人惊讶的是，苄基同系物在表型模型中能够调节EGFR磷酸化活性。这些数据表明LASSBio-并确定了它与EGFR的结合模式，这可能有助于先导优化研究。 2070（[具体化合物]）作为微管蛋白和EGFR的推定双重抑制剂。通过分子对接确定了它与EGFR的结合模式，这可能有助于先导优化研究。
