CRYSTALLOGRAPHIC STUDIES ON RETINOIDAL-ACTIVE AND RETINOIDAL-INACTIVE AROMATIC ANILIDES

Among various chemical classes of compounds with retinoidal activity, the retinobenzoic acid system having a 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl moiety and a benzoic acid moiety at opposite ends of the molecule has proved to be one of the most promising leads. Many retinoidal-active compounds with various kinds of chemical moieties as the linking group between the above two groups were synthesized, and amide moieties proved to be excellent linkages for potent retinoidal activities. The activities, however, were diminished by methylation at the amide nitrogen. To elucidate the reasons for the loss of the activities, we performed X-ray crystal structure analyses of three free amides and the corresponding three N-methylamide compounds. It was proved that all the free amide molecules take an extended trans conformation, whereas all the N-methylamide molecules take a folded cis conformation in the crystalline state. In combination with spectroscopic studies (UV and NMR), the above results suggested that these N-methylamides adopt remarkable folded conformations compared to the free amide molecules in solution. These facts strongly indicate that all these N-methylamides take cis conformations not only in the crystal but also in solution. It is the extended trans conformation that is required for specific binding to the retinoidal receptor macromolecule. Consequently, the loss of activities in N-methylamides seem to be ascribed to conformational factors but not to steric hindrance by the methyl group which might prevent binding to the target receptor. © 1990, American Chemical Society. All rights reserved.