Practical synthesis of a chromene analog for use as a retinoic acid receptor alpha antagonist lead compound

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.

Figure optionsDownload as PowerPoint slideHighlights
► A prototype compound for retinoic acid receptor (RAR) antagonist libraries.
► Modified synthesis of chromene RAR antagonists with increased yields and fewer steps.
► Mechanistic overview of a Grignard promoted ring opening and cyclization.
► A cell-based promoter assay for RARα comparing the prototype and a known antagonist.
► A binding mode for the prototype in RARα.