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

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. The detailed structure‐activity relationship (SAR) at the hydrophobic moiety of retinoids was investigated using silyl functionalities. 3‐tert‐Butyldimethylsilyl derivative 24 c exhibited potent HL‐60 cell differentiation‐inducing activity. Compound 24 c exhibited agonistic activity towards all three subtypes of retinoic acid receptor (RAR), with the highest activity towards RARγ.