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.

     

Silicon analogues of the retinoid agonists TTNPB and 3-methyl-TTNPB, disila-TTNPB and disila-3-methyl-TTNPB: chemistry and biology

Twofold sila-substitution (C/Si exchange) in the saturated ring of the tetrahydronaphthalene skeleton of the retinoid agonists TTNPB (1 a) and 3-methyl-TTNPB (2 a) leads to disila-TTNPB (1 b) and disila-3-methyl-TTNPB (2 b), respectively. The silicon compounds 1 b and 2 b were synthesized in multiple steps, and their identities were established by elemental analyses, multinuclear NMR experiments, and single-crystal X-ray diffraction studies. Like TTNPB (1 a) and 3-methyl-TTNPB (2 a), the analogous silicon-based arotinoids 1 b and 2 b are strong pan-RAR agonists and display the same strong differentiation and apoptosis-inducing activity in NB4 promyelocytic leukemia cells as the parent carbon compounds. These results are in keeping with the nearly isomorphous structures of 1 a and 1 b bound to the complex of the RARbeta ligand-binding domain with the nuclear receptor (NR) box 2 peptide of the SRC-1 coactivator. The contacts within the ligand-binding pocket are identical except for helix H11, for which two turns are shifted in the disila-TTNPB (1 b) complex. This study represents the first comprehensive structure-function analysis of a carbon/silicon switch in a signaling molecule and demonstrates that silicon analogues can have the same biological functionalities and conserved structures as their parent carbon compounds, and it illustrates at the same time that silicon analogues of biologically active compounds have the potential to induce alternative allosteric effects, as in the case of helix H11, which might allow for novel options in drug design.     

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 SiCH₂CH₂Si 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.     

Sila-haloperidol, a silicon analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate

Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.