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 hRXRalpha 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.
Lippert
W Peter
WP
Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074 Würzburg, Germany.
Burschka
Christian
C
Götz
Kathrin
K
Kaupp
Martin
M
Ivanova
Diana
D
Gaudon
Claudine
C
Sato
Yoshiteru
Y
Antony
Pierre
P
Rochel
Natacha
N
Moras
Dino
D
Gronemeyer
Hinrich
H
Tacke
Reinhold
R
D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000494:pharmacology*; D012825:Silicon / Q000737:chemistry* / Q000494:pharmacology; D055672:Static Electricity
D001565:Benzoates; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; C087130:SR 11237; D012825:Silicon