title: Silicon analogues of the RXR-selective retinoid agonist SR11237 (BMS649): chemistry and biology.
abstract: 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.
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074 Würzburg, Germany.
authors.forename: W Peter
authors.initials: WP
authors.lastname: Lippert
authors.forename: Christian
authors.initials: C
authors.lastname: Burschka
authors.forename: Kathrin
authors.initials: K
authors.lastname: Götz
authors.forename: Martin
authors.initials: M
authors.lastname: Kaupp
authors.forename: Diana
authors.initials: D
authors.lastname: Ivanova
authors.forename: Claudine
authors.initials: C
authors.lastname: Gaudon
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sato
authors.forename: Pierre
authors.initials: P
authors.lastname: Antony
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
authors.forename: Dino
authors.initials: D
authors.lastname: Moras
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Reinhold
authors.initials: R
authors.lastname: Tacke
mesh_terms: 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
chemical_list: D001565:Benzoates; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; C087130:SR 11237; D012825:Silicon