Synthesis and Biological Evaluation of Quercetagetin Derivatives as the Inhibitors of Mcl-1 and Bcl-2 Against Leukemia

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 <b>2a</b>-<b>2t</b>, <b>3a</b>-<b>3j</b> and <b>4a</b>-<b>4g</b>) and evaluated their anticancer activities on four leukemia cells (U937, K562, K562R and KG-1). Among those synthesized derivatives, compounds <b>2a</b> exhibited the best antiproliferative activity (IC₅₀ = 0.276, 0.159, 0.312 and 0.271 µM to U937, K562, K562R and KG-1, respectively). In addition, <b>2a</b> induced apoptosis in K562 and markedly arrested the cell cycle G2/M phase of K562. The Western blot assay showed that <b>2a</b> is a potential inhibitor that can effectively suppress the expression of Bcl-2 and Mcl-1. The molecular docking study predicted that <b>2a</b> had firm interactions with the active pockets of Bcl-2 and Mcl-1. Finally, in silico pharmacokinetic evaluation of <b>2a</b> indicated its potential as an anti-leukemia drug lead in the future.