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

SR11237 (BMS649, 4a) is a pan-RXR-selective retinoid agonist. Its silicon analogue, disila-SR11237 (4b; 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 5a and 5b, with an indane (disila-indane) instead of a tetraline (disila-tetraline) skeleton, were synthesized. The C/Si pairs 4a/4b and 5a/5b 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 5a resulted in a 10-fold increase in biological activity of the corresponding silicon-containing rexinoid 5b, 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 5a 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 5b 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.