Structure-activity relationship (SAR) study of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and the potential of the lead against multidrug resistance in cancer treatment.

Journal of Medicinal Chemistry
Gopalakrishnan AridossChengguo Xing

Abstract

Multidrug resistance (MDR) against standard therapies poses a serious challenge in cancer treatment, and there is a clinical need for new anticancer agents that would selectively target MDR malignancies. Our previous studies have identified a 4H-chromene system, CXL017 (4) as an example, that can preferentially kill MDR cancer cells. To further improve its potency, we have performed detailed structure-activity relationship (SAR) studies at the 3, 4, and 6 positions of the 4H-chromene system. The results reveal that the 3 and 4 positions prefer rigid and hydrophobic functional groups while the 6 position prefers a meta or para-substituted aryl functional group and the substituent should be small and hydrophilic. We have also identified and characterized nine MDR cancer cells that acquire MDR through different mechanisms and demonstrated the scope of our new lead, 9g, to selectively target different MDR cancers, which holds promise to help manage MDR in cancer treatment.

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Citations

May 21, 2013·Journal of Molecular Graphics & Modelling·Ningning HeSukjoon Yoon
Sep 21, 2013·Future Medicinal Chemistry·Shivaputra A PatilDuane D Miller
Oct 3, 2020·Cells·Luca PagliaroGiovanni Roti
Sep 18, 2020·Angewandte Chemie·Xinlan A F CookMichael C Willis
Jan 8, 2021·Journal of Hematology & Oncology·Luca PagliaroGiovanni Roti
Jun 22, 2020·European Journal of Medicinal Chemistry·Tingting LiuChengcai Xia
Feb 8, 2020·Journal of Medicinal Chemistry·Tanaji T Talele
Mar 29, 2014·Chemical Reviews·Madhu AeluriPrabhat Arya
Aug 26, 2020·Organic Letters·Aidan M KellyMartin D Burke

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