Conformational Analysis and Steric Contributions of 9-cis-Retinoic Acid Analogs

Tracy P. Hamilton, Bryan D. Cox, Kenneth F. Nguyen and Donald D. Muccio, Department of Chemistry, University of Alabama-Birmingham

9-cis-UAB30 is a novel retinoid analog of 9-cis-retinoic acid that is approaching clinical trials for cancer prevention.  When retinoic acid binds to the retinoic nuclear X receptor (RXR), there is significant twisting about the C8-C9 bond. The stable conformations of UAB30 and substituted butadienes have been examined using a calculated torsion potential curve along the C8-C9 torsion.  The energy, E, was calculated after a constrained geometry optimization as a function of the torsion angle, φ, at the B3LYP/6-31G* level of theory.  For UAB30 it was found that the most energetically favorable torsion angle was +/-50° (+/- s-gauche) and is dependant on the conformation of the ring system.  Another favorable conformation was found at 180° (s-trans) which is 1.3 kcal/mol greater in energy than the global minimum at s-gauche.  A barrier of 3.0 kcal/mol separates the global minimum at s-gauche from s-trans, and a much larger barrier at 0° separates the (+)-gauche from the (-)-gauche conformations.  Populations of 9-cis-UAB30 were calculated using a normalized Boltzmann distribution.  The populations for s-gauche and s-trans were found to be 82% and 18%, respectively.  Using the methods described by Guo and Karplus, a series of diene models were used to analyze the steric effects that contribute to the torsion potential curve of 9-cis-UAB30.

Oral