Synthesis and preliminary evaluation of affinity to retinoic acid receptors for new organosilicon-based retinoids

Facile synthetic routes to new silicon-containing ligands (1-4) for retinoic acid receptors (RARs) are reported. The design of these RAR ligands is based on a pharmacophoric model that divides the molecules into three regions (A, B, and C). The series of ligands is unique in region A due to their acyclic nature and the presence of alkyl-substituted silicon at the core. Substituted silyl groups that are generally viewed as protecting groups are used to fulfill pharmacophore requirements. Various alkyl substituents available on the silicon starting materials afford an opportunity to explore steric effects on binding. In region B of ligands 1-4, a cinnamate moiety maintains some degree of conjugation and planarity in the molecules. A biaryl group used in region B of another series of compounds is reported to lead to RARb selectivity. Finally, region C of the ligands contains a carboxylate group, a well know pharmacophore requirement for RAR ligands. The compounds prepared in this work were found to have micromolar to nanomolar affinity for these medically relevant target receptors. The proposed silane-containing ligands 'represent a new series of siloacetylenic aryl acids that are worth of further investigation. They may serve as leads for the development of higher-affinity, more receptor-selective agents.