Structural Development of Silicon-Containing Retinoids: Structure-Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities.

ABSTRACT

We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure-activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t-butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription-promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα-selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype-selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.