Li Kang, Ge Xiaomei, Liu Wei, Huang Lei, Lv Xinye, Tang Yuhui, He Zhehao, Yang Yingxue, Chen Miaofen, Zeng Jianguo, Cheng Pi
Hunan Key Laboratory of Traditional Chinese Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China.
Chinese Medicinal Materials Breeding Innovation Center of Yuelushan Laboratory, Changsha 410128, China.
Int J Mol Sci. 2025 Mar 18;26(6):2727. doi: 10.3390/ijms26062727.
B-cell lymphoma-2 (Bcl-2) family proteins are fundamental regulators of intrinsic cell apoptosis, and overexpression of apoptotic proteins (Bcl-2 and Mcl-1) is a characteristic of many haematological malignancies. Thus, it is necessary to discover novel inhibitors to treat leukemia. In the current study, we synthesized a series of quercetagetin derivatives (compounds -, - and -) and evaluated their anticancer activities on four leukemia cells (U937, K562, K562R and KG-1). Among those synthesized derivatives, compounds exhibited the best antiproliferative activity (IC = 0.276, 0.159, 0.312 and 0.271 µM to U937, K562, K562R and KG-1, respectively). In addition, induced apoptosis in K562 and markedly arrested the cell cycle G2/M phase of K562. The Western blot assay showed that is a potential inhibitor that can effectively suppress the expression of Bcl-2 and Mcl-1. The molecular docking study predicted that had firm interactions with the active pockets of Bcl-2 and Mcl-1. Finally, in silico pharmacokinetic evaluation of indicated its potential as an anti-leukemia drug lead in the future.
B细胞淋巴瘤-2（Bcl-2）家族蛋白是细胞内源性凋亡的基本调节因子，凋亡蛋白（Bcl-2和Mcl-1）的过表达是许多血液系统恶性肿瘤的一个特征。因此，有必要发现新型抑制剂来治疗白血病。在本研究中，我们合成了一系列槲皮万寿菊素衍生物（化合物-、-和-），并评估了它们对四种白血病细胞（U937、K562、K562R和KG-1）的抗癌活性。在这些合成衍生物中，化合物表现出最佳的抗增殖活性（对U937、K562、K562R和KG-1的IC分别为0.276、0.159、0.312和0.271μM）。此外，诱导K562细胞凋亡，并显著使K562细胞周期停滞于G2/M期。蛋白质免疫印迹分析表明，是一种潜在的抑制剂，可有效抑制Bcl-2和Mcl-1的表达。分子对接研究预测，与Bcl-2和Mcl-1的活性口袋有紧密相互作用。最后，对的计算机模拟药代动力学评估表明其未来作为抗白血病药物先导物的潜力。
