UFSCar - Univ Federal de São Carlos, Departamento de Química, São Carlos, Brazil.
UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Geral e Inorgânica, Araraquara, Brazil.
J Inorg Biochem. 2019 Oct;199:110725. doi: 10.1016/j.jinorgbio.2019.110725. Epub 2019 Jun 6.
Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-IIα (TOP2A) towards four novel Pd(II)-complexes bearing N,S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25-25μM. These results exhibited more effectivity than anticancer agent etoposide (35μM) and merbarone (40-50μM). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Cal27 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC=1.81-4.46μM). As well, 1-4 exhibited their selectivity index (SI) higher than cisplatin against HEK-293 (human kidney) normal cells, at least 11.6-fold (SI=1.4-5.0; SI=0.12). Further, Red Blood Cell hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor.
本文采用低成本工作流程开发了一种稳健的对接方案，重点研究了四个新型 Pd(II)配合物对人拓扑异构酶-IIα（TOP2A）ATP 酶结构域的调节作用，这些配合物均含有 N、S 供体配体。体外 TOP2A 抑制试验证实，这些配合物能够以 6.25-25μM 的浓度范围阻止酶的功能。这些结果比抗癌药物依托泊苷（35μM）和米托蒽醌（40-50μM）更有效。通过 Resazurin 试验对 MCF-7、MDA-MB-231（人乳腺癌）、DU-145（人前列腺）、A549（人肺）和 Cal27（人舌）肿瘤细胞系进行筛选，结果显示这些化合物具有很强的细胞毒性作用，主要针对 MCF-7（IC=1.81-4.46μM）。此外，化合物 1-4 对 HEK-293（人肾）正常细胞的选择性指数（SI）高于顺铂，至少为 11.6 倍（SI=1.4-5.0；SI=0.12）。进一步的，红细胞溶血试验表明，先前被评估为 TOP2A 抑制剂中最有效的化合物 4 在体外具有非毒性特征。
