PDF(Pubmed)
Abstract：
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 μΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
摘要：
谷胱甘肽转移酶P1-1（hGSTP1-1）极大地影响了癌细胞中的多药耐药（MDR）机制。使用合成或天然化合物作为hGSTP1-1抑制剂被认为是克服MDR的有效方法。合成了由与查尔酮衍生物连接的香豆素-6-磺酰胺组成的9种化合物，并评估了它们抑制hGSTP1-1的能力。在合成衍生物中，化合物5g,5f,5a显示出最有效的抑制作用，IC50值为12.2±0.5μM，分别为12.7±0.7和16.3±0.6。最有效分子的动力学抑制分析，5g,表明它表现为目标酶的混合型抑制剂。5a的体外细胞毒性评估，5f,和5g对人前列腺癌细胞系DU-145和PC3以及乳腺癌细胞系MCF-7表明化合物5g对所有测试的细胞系表现出最显著的细胞毒性作用。进行了分子对接研究以预测5g的结构和分子决定因素，5f,和5a结合hGSTP1-1。与实验数据一致，结果表明，由于形状互补性，5g在三种研究的抑制剂中表现出最低的对接分数，由范德华统治,氢键和π-π堆叠相互作用。这些发现表明，香豆素-查尔酮杂种为开发安全有效的基于天然产物的敏化剂提供了新的视角，这些敏化剂可以靶向hGSTP1-1用于抗癌目的。
