Department of Biological Sciences, METU, Ankara, Turkiye.
Division of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara, Turkiye.
Drug Dev Res. 2024 Nov;85(7):e70008. doi: 10.1002/ddr.70008.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, driven mainly by chronic hepatitis infections and metabolic disorders, which highlights the urgent need for novel therapeutic strategies. Sirtuins, particularly SIRT1 are crucial in HCC pathogenesis, making it a promising drug target. Indole-based molecules show potential as therapeutic agents by interacting with key proteins like sirtuins involved in cancer progression. In this study, we designed and synthesized novel indole-based small molecules and investigated their potential sirtuin inhibitory action and anticancer activity on HCC cell lines. Four of the twenty-eight tested small molecules on different cancer types were selected (4 g, 4 h, 4o, and 7j) based on their structure-activity relationship and studied on a panel of HCC cell lines. Compounds had active drug-target interactions with SIRT1 or SIRT2 based on DEEPScreen DTI predictions and docking studies which confirmed that 4o, 4 g, and 7j were most potent in their interaction with SIRT1. Compound 4 g caused the highest sirtuin activity inhibition in vitro and induced G1 arrest and apoptosis in HCC cell lines.
肝细胞癌 (HCC) 是全球癌症相关死亡的主要原因，主要由慢性肝炎感染和代谢紊乱驱动，这凸显了对新型治疗策略的迫切需求。Sirtuins，特别是 SIRT1，在 HCC 的发病机制中起着关键作用，使其成为一个有前途的药物靶点。吲哚类分子通过与涉及癌症进展的关键蛋白（如 sirtuins）相互作用，显示出作为治疗剂的潜力。在这项研究中，我们设计并合成了新型的吲哚类小分子，并研究了它们对 HCC 细胞系的潜在的 sirtuin 抑制作用和抗癌活性。根据结构-活性关系，从 28 种不同类型癌症的测试小分子中选择了四种（4g、4h、4o 和 7j），并在一系列 HCC 细胞系上进行了研究。基于 DEEPScreen DTI 预测和对接研究，化合物与 SIRT1 或 SIRT2 具有活性药物-靶相互作用，证实 4o、4g 和 7j 在与 SIRT1 的相互作用中最有效。化合物 4g 在体外引起最高的 sirtuin 活性抑制，并诱导 HCC 细胞系中的 G1 期阻滞和细胞凋亡。
