Total synthesis and RXRα-mediated transcription studies of neriifolone B and related compounds

Neriifolone B (1), a natural product containing a novel 4′,4′-dimethyl-4′,5′-dihydropyran-6-one[2′,3′:3,4]xanthone skeleton, was found to be a potent inhibitor of transcription mediated by retinoid X receptor α (RXRα). The first total synthesis of neriifolone B (1) was achieved in 14 steps with an overall yield of 7.1%. A Claisen rearrangement was employed as the key step in the sequence. The activity of six natural xanthones and eight compounds related to neriifolone B (1) against RXRα-mediated transcription was evaluated. Two neriifolone B analogs, 17 and 11″, were potent inhibitors of RXRα transcriptional activity. Preliminary structure-activity relationship studies are discussed briefly.