Silicon Analogues of the RXR‐Selective Retinoid Agonist SR11237 (BMS649): Chemistry and Biology

C/Si switch : Twofold sila‐substitution (C/Si exchange) in the RXR‐selective retinoids 4 a (SR11237) and 5 a leads to 4 b (disila‐SR11237) and 5 b , respectively. Chemistry and biology of the C/Si pairs are reported.SR11237 (BMS649, 4 a ) is a pan‐RXR‐selective retinoid agonist. Its silicon analogue, disila‐SR11237 ( 4 b ; twofold C/Si exchange), was prepared in a multistep synthesis by starting from 1,2‐bis(ethynyldimethylsilyl)ethane. In addition, the related C/Si analogues 5 a and 5 b , with an indane (disila‐indane) instead of a tetraline (disila‐tetraline) skeleton, were synthesized. The C/Si pairs 4 a / 4 b and 5 a / 5 b were studied for their interaction with retinoid receptors and were demonstrated to be highly potent RXR‐selective (“rexinoid”) agonists. Interestingly, twofold C/Si exchange in the indane moiety of 5 a resulted in a 10‐fold increase in biological activity of the corresponding silicon‐containing rexinoid 5 b , possibly resulting from an increased receptor affinity or a divergent allosteric effect on co‐regulator‐binding surfaces. The crystal structures of the ternary complexes formed by 5 a and 5 b , respectively, with the ligand‐binding domain of hRXRα and a peptide of the co‐activator TIF2/GRIP1 revealed additional interactions of the disila analogue 5 b with the H7 and H11 residues, supporting the first option of increased binding affinity. This is the first demonstration of an increase in binding affinity of a ligand to a nuclear receptor by C/Si replacement, thereby adding this C/Si switch strategy to the repertoire of nuclear receptor ligand design.