Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (K_i = 0.21 ± 0.02 μM, IC₅₀ = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.

髓细胞白血病-1 (Mcl-1) 是一种经过验证且有吸引力的癌症治疗靶点。Mcl-1 在许多癌症中的过度表达使癌细胞能够逃避细胞凋亡，并有助于它们对当前的化疗药物产生抵抗力。在这项研究中，设计和合成了三十多种具有不同取代基的香豆素衍生物，并使用基于荧光偏振的结合测定评估了它们的 Mcl-1 抑制活性。结果表明，邻苯二酚基团是香豆素抑制Mcl-1活性的关键组成部分，邻苯二酚基团的甲基化导致抑制活性降低。在6,7-二羟基香豆素的C-4位引入疏水吸电子基团，增强了Mcl-1的抑制能力，并且该位置的亲水基团对抑制效力无益。此外，在 C-5 或 C-8 位置引入含氮基团，允许分子内氢键，也不利于 Mcl-1 抑制。在所有测试的香豆素中，4-三氟甲基-6,7-二羟基香豆素（Cpd4 ) 对 Mcl-1 显示出最有效的抑制活性（分别为K _i = 0.21 ± 0.02 μM，IC ₅₀ = 1.21 ± 0.56 μM），因此在 A549 细胞中也验证了对紫杉醇抗性的有益作用。在对接模拟中，Cpd 4和 Mcl-1之间的强相互作用进一步支持了观察到的 Cpd 4强效 Mcl-1 抑制能力。所有测试的香豆素衍生物的 3D-QSAR 分析进一步提供了对 Mcl-1 的抑制作用与香豆素的空间静电特性之间关系的新见解。这些发现对于药物化学家设计和开发用于生物医学应用的更有效的 Mcl-1 抑制剂可能具有重要价值。