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Synthesis and structure-activity relationship of coumarins as potent Mcl-1 inhibitors for cancer treatment
Yang-Liu Xia1, Jing-Jing Wang2, Shi-Yang Li3
1School 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.
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 microM, IC50 = 1.21 ± 0.56 microM, 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.
Insights
New coumarin derivatives show potent inhibition of myeloid cell leukemia-1 (Mcl-1), a key target in cancer therapy. The compound 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) demonstrated significant Mcl-1 inhibition and reduced taxol resistance in cancer cells.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Myeloid cell leukemia-1 (Mcl-1) overexpression promotes cancer cell survival and chemoresistance.
- Targeting Mcl-1 is a promising strategy for developing novel cancer therapeutics.
Purpose of the Study:
- To design, synthesize, and evaluate novel coumarin derivatives as Mcl-1 inhibitors.
- To identify key structural features responsible for Mcl-1 inhibitory activity.
- To assess the therapeutic potential of lead compounds in overcoming drug resistance.
Main Methods:
- Synthesis of over thirty coumarin derivatives with diverse substituents.
- Fluorescence polarization-based binding assays to determine Mcl-1 inhibitory activity.
- Cell-based assays to evaluate drug resistance reversal (e.g., taxol resistance in A549 cells).
- Molecular docking simulations and 3D-QSAR analysis for structure-activity relationship studies.
Main Results:
- The catechol group is crucial for Mcl-1 inhibitory activity; methylation reduced potency.
- Hydrophobic electron-withdrawing groups at the C-4 position enhanced Mcl-1 inhibition.
- Hydrophilic groups at C-4 and nitrogen-containing groups at C-5/C-8 were unfavorable for inhibition.
- 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) exhibited the most potent Mcl-1 inhibition (Ki = 0.21 ± 0.02 µM, IC50 = 1.21 ± 0.56 µM).
- Cpd 4 demonstrated efficacy in overcoming taxol resistance in A549 cells.
- Docking simulations and 3D-QSAR provided insights into Mcl-1-coumarin interactions and structure-activity relationships.
Conclusions:
- Coumarin derivatives, particularly Cpd 4, are effective Mcl-1 inhibitors.
- Structural modifications, such as incorporating hydrophobic groups at C-4, can optimize inhibitory potency.
- These findings offer valuable guidance for designing advanced Mcl-1 inhibitors for cancer therapy.
- Cpd 4 shows potential for clinical development to combat Mcl-1-mediated drug resistance.
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