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Silicon Analogues of the RXR‐Selective Retinoid Agonist SR11237 (BMS649): Chemistry and Biology
Author(s) -
Lippert W. Peter,
Burschka Christian,
Götz Kathrin,
Kaupp Martin,
Ivanova Diana,
Gaudon Claudine,
Sato Yoshiteru,
Antony Pierre,
Rochel Natacha,
Moras Dino,
Gronemeyer Hinrich,
Tacke Reinhold
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900090
Subject(s) - indane , chemistry , retinoid x receptor , stereochemistry , allosteric regulation , ligand (biochemistry) , agonist , moiety , receptor , nuclear receptor , biochemistry , transcription factor , gene
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.