Inhibition of papilloma formation by analogues of 7,8-dihydroretinoic acid

The design of analogues of 7,8-dihydroretinoic acid (7,8-dihydro-RA) was based on reported biological activities of this retinoid and its dihydro-TMMP(1) analogue and on structural hypotheses. 7-Oxa-7,8-dihydroretinoids (5, 6) were prepared by O-alkylation of phenoxides by methyl 8-bromo-3,7-dimethyl-2,4,6-octatrienoate. In some cases, C-alkylation also occurred. 7-Aza-8-oxo-7,8-dihydroretinoids (12, 13) were synthesized from benzeneamines and the acyl cyano or bromo derivative of the monomethyl ester of 3,7-dimethyl-2,4,6-octatriene-1,8-dioic acid. These monomethyl ester precursors were synthesized from the known analogous aldehyde via an O-trimethylsilyl cyanohydrin. 7-(2,3,5-Trimethylphenoxy)-3,5-dimethyl-2,4,6-octatrienoic acid (6b) was the most active of the 7-oxa-7,8-dihydro-RAs in inhibiting DMBA-initiated and TPA-promoted mouse-skin papillomas. The ED(50) was about 4-fold that of etretinate. Two additional 7-oxa-7,8-dihydro-RAs exhibited modest activity in the papilloma assay. Some of the 7-oxa-7,8-dihydro-RAs bind to CRABP and RARalpha.