2. Academic Validation
  3. Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment

Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment

  • Bioorg Med Chem. 2021 Jan 1:29:115851. doi: 10.1016/j.bmc.2020.115851.
Yang-Liu Xia 1,  Jing-Jing Wang 2,  Shi-Yang Li 3,  Yong Liu 2,  Frank J Gonzalez 4,  Ping Wang 5,  Guang-Bo Ge 6
Affiliations

Affiliations

  • 1 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.
  • 2 School of Life Science and Medicine, Dalian University of Technology, Panjin 124221, China.
  • 3 Analytical Central Laboratory, Shengyang Harmony Health Medical Laboratory Co Ltd, Shenyang 210112, China.
  • 4 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 5 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: wangping12@dicp.ac.cn.
  • 6 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
PMID: 33218896 DOI: 10.1016/j.bmc.2020.115851
Abstract

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 (Ki = 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.

Keywords

Coumarins; Myeloid cell leukemia-1 (Mcl-1); Structure-activity relationship (SAR).

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