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Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound
Rachael Jetson1, Neha Malik, Amarjit Luniwal
1Center for Drug Design and Development, Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH 43606, USA.
Abstract:
Retinoic acid receptor alpha (RARα) selective compounds may guide the design of drugs that can be used in conjunction with hormonal adjuvant therapy in the treatment of breast cancer. Herein we report a modified synthesis of a known RARα antagonist, 2-fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid and a synthesis of its unknown, desfluoro analog, 4-[[[8-bromo-2,2-dimethyl-4-(4-methylphenyl)chroman-6-yl]carbonyl]amino]benzoic acid. The modified route allows for facile reaction workups, increased yields, lower cost and incorporates a green alternative step. Structure-activity relationship studies determined through functional cell-based assays, demonstrated antagonism to RARα for both compounds. Molecular modeling within the RARα binding pocket was used to compare binding interactions of the desfluoro analog to a known RAR antagonist.
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