Bozok University, Faculty of Arts and Sciences, Department of Chemistry, Yozgat, Turkey.
Gaziosmanpaşa University, Faculty of Natural Sciences and Engineering, Department of Bioengineering, Tokat, Turkey.
Eur J Med Chem. 2016 Oct 21;122:280-290. doi: 10.1016/j.ejmech.2016.06.032. Epub 2016 Jun 23.
Invasive ductal carcinoma is the most common breast malignancies tumors and has tendency to bone metastases. Many oncogenic client proteins involved in formation of metastatic pathways. Stabilization, regulation, and maintenance of these oncogenic client proteins are provided with Heat Shock Protein 90 (Hsp90). Hsp90 perform these processes through its ATP binding and subsequent hydrolysis energy. Therefore, designing Hsp90 inhibitors is a novel cancer treatment method. However, many Hsp90 inhibitors have solubility problems and showed adverse effects in clinical trials. Thus, we designed and synthesized novel pyrimidinyl acyl thiourea derivatives to selectively inhibit Hsp90 alpha in human invasive ductal breast (MCF-7) and human bone osteosarcoma (Saos-2) cell lines. In vitro experiments showed that the compounds inhibited cell proliferation, ATP hydrolysis, and exhibited cytotoxic effect on these cancer cell lines. Further, gene expression was analyzed by microarray studies on MCF-7 cell lines. Several genes that play vital roles in breast cancer pathogenesis displayed altered gene expression in the presence of a selected pyrimidinyl acyl thiourea compound. Molecular docking studies were also performed to determine interaction between Hsp90 ATPase domain and pyrimidinyl acyl thiourea derivatives. The results indicated that the compounds are able to interact with Hsp90 ATP binding pocket and inhibit ATPase function. The designed compounds powerfully inhibit Hsp90 by an average of 1 μM inhibition constant. And further, the compounds perturb Hsp90 N terminal domain proper orientation and ATP may not provide required conformational change for Hsp90 function as evidenced by in silico experiments. Therefore, the designed compounds effectively inhibited both invasive ductal breast carcinoma and bone metastasis. Pyrimidinyl acyl thiourea derivatives may provide a drug template for effective treatment of invasive ductal breast carcinoma and its bone metastasis as well as new therapeutic perspective for drug design.
浸润性导管癌是最常见的乳腺恶性肿瘤，有发生骨转移的倾向。许多致癌客户蛋白参与形成转移途径。热休克蛋白 90（Hsp90）为这些致癌客户蛋白的稳定性、调节和维持提供了条件。Hsp90 通过其 ATP 结合和随后的水解能量来完成这些过程。因此，设计 Hsp90 抑制剂是一种新的癌症治疗方法。然而，许多 Hsp90 抑制剂存在溶解度问题，并在临床试验中表现出不良反应。因此，我们设计并合成了新型嘧啶酰基硫脲衍生物，以选择性抑制人浸润性导管乳腺癌（MCF-7）和人骨肉瘤（Saos-2）细胞系中的 Hsp90α。体外实验表明，这些化合物抑制细胞增殖、ATP 水解，并对这些癌细胞系表现出细胞毒性作用。此外，还通过 MCF-7 细胞系的微阵列研究分析了基因表达。在存在选定的嘧啶酰基硫脲化合物的情况下，一些在乳腺癌发病机制中起重要作用的基因显示出改变的基因表达。还进行了分子对接研究，以确定 Hsp90 ATP 酶结构域与嘧啶酰基硫脲衍生物之间的相互作用。结果表明，这些化合物能够与 Hsp90 ATP 结合口袋相互作用并抑制 ATP 酶功能。设计的化合物通过平均 1 μM 的抑制常数强力抑制 Hsp90。此外，化合物扰乱了 Hsp90 N 端结构域的适当取向，并且 ATP 可能不会为 Hsp90 功能提供所需的构象变化，这一点通过计算机实验得到了证明。因此，设计的化合物有效地抑制了浸润性导管乳腺癌和骨转移。嘧啶酰基硫脲衍生物可为有效治疗浸润性导管乳腺癌及其骨转移提供药物模板，并为药物设计提供新的治疗视角。
