HYDROGEN BOND INTERACTIONS AND THEIR INFLUENCE ON CONFORMATION OF RETINOIDAL-ACTIVE AND INACTIVE AROMATIC ANILIDES. Qi Gao, Kuo-Long Yu, Simon Chen,⁺ Jacek Ostrowski,⁺ John E. Starret Jr., Kenneth M. Tramposch,⁺ Peter R. Reczek,⁺ Muzammil M. Mansuri, Kevin J. Volk and Mike S. Lee, Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. ⁺Westwood-Squibb Pharmaceuticals, 100 Forest Avenue, Buffalo, NY 14213, USA

Am 580 is a potent synthetic retinoic acid derivative showing selectivity towards one of the retinoic acid receptors, RAR [[alpha]]. Previous studies on the structure-activity relationship and single-crystal analyses of Am580 and its analogs have concluded that their bioactivity is conformation dependent. An extended trans conformation is required for specific binding to the retinoidal receptors and the loss of activity seems to be ascribed to a remarkable folded cis conformation. For a better understanding of the relationship between activity and conformation, we have synthesized a series of fluorinated and alkoxy substituted Am580 retinoids and examined their 3-dimensional structures by X-ray crystallography. All these molecules assume extended conformations in solid state while showing quite different in vitro and in vivo activity from the parent molecule Am580. This observation confirms that this amide moiety linkage indeed regulates the positional relation between the two groups at opposite ends of the molecules to give a trans conformation. However, there are pronounced differences in conformation which are apparently due to different intra- and intermolecular hydrogen bonding interactions involving the functional groups between the neighboring molecules in small molecule crystals. The geometric data of these interactions are consistent with relative intramolecular hydrogen bond strengths ranked in parallel infrared and NMR studies, suggesting a similarity of conformation in solid state and in solution. A detailed analysis of these hydrogen bonds is thus expected to provide some insight into the interactions between the retinoids and the receptors when forming complexes.