School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China.
Bioorg Med Chem. 2021 Jan 1;29:115851. doi: 10.1016/j.bmc.2020.115851. Epub 2020 Nov 7.
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 = 0.21 ± 0.02 μM, IC = 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.
髓样细胞白血病-1（Mcl-1）是癌症治疗中一个经过验证且有吸引力的靶点。许多癌症中 Mcl-1 的过表达使癌细胞能够逃避细胞凋亡，并导致它们对当前化疗药物的耐药性。在这项研究中，设计并合成了 30 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法评估了它们对 Mcl-1 的抑制活性。结果表明，儿茶酚基团是香豆素抑制 Mcl-1 活性的关键组成部分，儿茶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 位置引入疏水性吸电子基团，增强了 Mcl-1 抑制能力，而在该位置引入亲水性基团则不利于抑制效力。此外，在 C-5 或 C-8 位置引入含氮基团，允许形成分子内氢键，也不利于 Mcl-1 的抑制。在所测试的所有香豆素中，4-三氟甲基-6,7-二羟基香豆素（Cpd 4）对 Mcl-1 表现出最强的抑制活性（K=0.21±0.02 μM，IC=1.21±0.56 μM），在 A549 细胞中也验证了其对紫杉醇耐药性的有益作用。对接模拟中 Cpd 4 与 Mcl-1 之间的强烈相互作用进一步支持了 Cpd 4 对 Mcl-1 抑制能力的观察结果。对所有测试的香豆素衍生物的 3D-QSAR 分析进一步提供了新的见解，了解了对 Mcl-1 的抑制作用与香豆素的空间静电性质之间的关系。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 抑制剂具有重要价值。
