Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment. (1st January 2021)

• Record Type: Journal Article
• Authors: Xia, Yang-Liu; Wang, Jing-Jing; Li, Shi-Yang; Liu, Yong; Gonzalez, Frank J.; Wang, Ping; Ge, Guang-Bo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 29(2021)
• Publication Date: 2021-01-01
• Subjects: Myeloid cell leukemia-1 (Mcl-1) -- Coumarins -- Structure-activity relationship (SAR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115851
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: The inhibitory effects of a series of structurally diverse coumarins on Mcl-1 were assayed. The structure-activity relationship of couamrins as Mcl-1 inhibitors were summarized. Docking simulations were conducted to explore the interactions between coumarins and Mcl-1. 3D-QSAR analysis provided new insights into the relationships between the Mcl-1 inhibitory effects and the steric-electrostatic properties of coumarins. 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 ( K i = 0.21 ± 0.02 μM, IC 50 = 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.