Exploring the structure–activity relationship and mechanism of a chromene scaffold (CXL series) for its selective antiproliferative activity toward multidrug-resistant cancer cells

Bian, Tengfei and Kavitha, C. V. and Wang, Yi and Meacham, Amy and Hati, Santanu and Cogle, Christopher R. and Sun, Haifeng and Xing, Chengguo (2018) Exploring the structure–activity relationship and mechanism of a chromene scaffold (CXL series) for its selective antiproliferative activity toward multidrug-resistant cancer cells. Journal of Medicinal Chemistry, 61 (15). pp. 6892-6903. ISSN 1520-4804

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Official URL: https://doi.org/10.1021/acs.jmedchem.8b00813

Abstract

Multidrug resistance (MDR) is one major barrier in cancer management, which urges for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate increased antiproliferative activity toward MDR acute-myeloid-leukemia (AML) cells. The structure–activity relationship (SAR) of the antiproliferative potency has been partly characterized, whereas the structural determinants contributing to selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells. The results not only confirmed previous SAR studies but also, for the first time, provided structural insights into the selectivity for MDR HL60/MX2 cells. Using the lead compounds as probes, we demonstrated that their modulation of intracellular-calcium homeostasis results in their antiproliferative potency and selectivity. Three candidates also demonstrate excellent in vitro safety profiles between cancer cells and normal cells, which will be evaluated in vivo in future studies.

Item Type: Article
Additional Information: PMID: 29995404
Subjects: C Chemical Science > Chemistry
Divisions: PG Centre Mandya
Depositing User: Manjula P Library Assistant
Date Deposited: 08 Jul 2019 06:41
Last Modified: 08 Jul 2019 06:41
URI: http://eprints.uni-mysore.ac.in/id/eprint/4866

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