Retinoidal Dienamides and Related Aromatic Amides. Replacement of the 9-Ene Structure of Retinoic Acid with a trans- or cis-Amide Group.

Abstract

Several retinoid candidates which possess an amide bond at the position corresponding to the 9-ene part of retinoic acid (1) were synthesized and their conformations and biological activities were investigated. N-(Methoxycarbonyl)dienamines, prepared by the rearrangement of dienoic acid azides trapped by methanol, were condensed with acid chlorides, followed by removal of the methoxycarbonyl group and hydrolysis of the ester group to afford the secondary dienamides, N-(2, 6, 6-trimethyl-1-cyclohexen-1-yl)muconamic acid (7a), 5-[[3-(2, 6, 6-trimethyl-1-cyclohexen-1-yl)-2-propenoyl]amino]-2, 4-pentadienoic acid (8a), and 4-[N-[2-[2, 6, 6-trimethyl-1-cyclohexen-1-yl)ethenyl]carbamoyl]benzoic acid (26a). The tertiary amide derivatives were also prepared by N-methylation of the secondary amides. NMR studies indicated that the secondary dienamides exist predominantly in trans-amide form in solution, like the potent retinoidal aromatic amide, 4-[(5, 6, 7, 8-tetrahydro-5, 5, 8, 8, -tetramethyl-2-naphthalenyl)-carbamoyl]benzoic acid (Am80). N-Methylation of the secondary amides resulted in cis-amide preference in solution. The biological activities of these amides were examined in terms of the differentiation-inducing activity towards human promyelocytic leukemia cell line HL-60.