Zwitterionic and anionic multinuclear pentacoordinate silicon(IV) complexes with bridging (R,R)-tartrato(4-) ligands and SiO5 skeletons: synthesis and reactivity in aqueous solution.

Two nutrients in one molecule: A zwitterionic λ(5)Si,λ(5)Si'-disilicate (1) was synthesized and characterized. It contains ligands that exclusively derive from natural products ((R,R)-tartaric acid, choline). Hydrolysis of 1 yields 2, which shows a remarkable kinetic stability in water. Upon dissolution of 1 and 2 in water, the nutrients choline and orthosilicic acid are formed by hydrolysis.

Novel silicon-containing analogues of the retinoid agonist bexarotene: syntheses and biological effects on human pluripotent stem cells.

Twofold sila-substitution (C/Si exchange) of the clinically used RXR-selective retinoid agonist bexarotene leads to disila-bexarotene, which displays pharmacological potency similar to that of the parent carbon compound, as shown in a HeLa-cell-based RXR assay. Formal exchange of the SiCH2CH2 Si group in disila-bexarotene with a SiCH2Si or SiOSi moiety leads to the disila-bexarotene analogues 8 and 9. The silicon compounds 8 and 9 were synthesized in multistep syntheses, starting from HC≡C(CH3)2SiCH2Si(CH3)2C≡CH and HC≡C(CH3)2SiOSi(CH3)2C≡CH, respectively. The key step in the syntheses of 8 and 9 is a cobalt-catalyzed [2+2+2] cycloaddition reaction that affords the 1,3-disilaindane and 2-oxa-1,3-disilaindane skeletons. Disila-bexarotene and its analogues 8 and 9 were studied for their biological effects relative to all-trans retinoic acid in cultured human pluripotent stem cells. The parent carbon compound bexarotene was included in some of these biological studies. Although the silicon-containing bexarotene analogues disila-bexarotene, 8, and 9 appear not to regulate the differentiation of TERA2.cl.SP12 stem cells, preliminary evidence indicates that these compounds may possess enhanced functions over the parent compound bexarotene, such as induction and regulation of cell death and cell numbers. The biological data obtained indicate that bexarotene, contrary to the silicon-containing analogues disila-bexarotene, 8, and 9, may partially act to induce cell differentiation.

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.