Multidrug resistance and toxic side effects are the major challenges in cancer treatment with microtubule-targeting agents (MTAs), and thus, there is an urgent clinical need for new therapies. Chalcone, a common simple scaffold found in many natural products, is widely used as a privileged structure in medicinal chemistry. We have previously validated tubulin as the anticancer target for chalcone derivatives. In this study, an α-methyl-substituted indole-chalcone (FC77) was synthesized and found to exhibit an excellent cytotoxicity against the NCI-60 cell lines (average concentration causing 50% growth inhibition = 6 nM). More importantly, several multidrug-resistant cancer cell lines showed no resistance to FC77, and the compound demonstrated good selective toxicity against cancer cells versus normal CD34 + blood progenitor cells. A further mechanistic study demonstrated that FC77 could arrest cells that relate to the binding to tubulin and inhibit the microtubule dynamics. The National Cancer Institute COMPARE analysis and molecular modeling indicated that FC77 had a mechanism of action similar to that of colchicine. Overall, our data demonstrate that this indole-chalcone represents a novel MTA template for further development of potential drug candidates for the treatment of multidrug-resistant cancers.
Bibliographical noteFunding Information:
This research was funded by grants from the Shanghai Municipal Commission of Health and Family Planning (2017YQ052 to C.Z.); the Young Elite Scientists Sponsorship Program by the China Association for Science and Technology (2017QNRC061 to C.Z.); the Key Research and Development Program of Ningxia (2018BFH02001 to W. Z. and 2018BFH02001-01 to C.Z.); the Shanghai “‘ChenGuang’” Project (16CG42 to C.Z.); the National Natural Science Foundation of China (81502978 to C.Z.); the National Cancer Institute, National Institutes of Health, USA (R01CA163864 to C.X.); Ningxia Medical University (XT2017022 to C.X.); the University of Minnesota Masonic Cancer Center and Academic Health Center Heme Malignancy Tissue Bank; and the National Heart, Lung, and Blood Institute, National Institutes of Health, USA (T32HL007062 to C.E.E.). We also thank Dr. Li Su for the cell cycle analysis.
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Copyright 2019 Elsevier B.V., All rights reserved.
- microtubule-targeting agent
- multidrug resistance