Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells

Abstract

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.

Design and synthesis of silicon-containing tubulin polymerization inhibitors: Replacement of the ethylene moiety of combretastatin A-4 with a silicon linker

“…13 In recent years, silicon-containing bioactive compounds have been reported. [14][15][16][17][18][19] The incorporation of silicon into organic compounds can improve various biological properties, including selectivity, potency, pharmacokinetics, pharmacodynamics and cell penetration. Indeed, several organosilicon agents have advanced to clinical studies.…”

Advances in drug design with RXR modulators

“…Disila-SR11237 4.3b caused a tenfold increase in the biological activity of the parent rexinoid and at low concentrations this compound was more potent than 9-cis-retinoic acid 2.1 [67]. Other disilarexinoids with a smaller hydrophobic ring 4.4 [67] have been tested in cultured human pluripotent stem cells together with bexarotene 2.2 and all-trans-retinoic acid. Silicon derivatives 4.4 did not induce the differentiation of the TERA2.cl.…”

“…The disila analogues of 3-Me-TTNPB 4.2a and SR11237 4.3a, compounds 4.2b and 4.3b, respectively, have also been synthesized [66]. Disila-SR11237 4.3b caused a tenfold increase in the biological activity of the parent rexinoid and at low concentrations this compound was more potent than 9-cis-retinoic acid 2.1 [67]. Other disilarexinoids with a smaller hydrophobic ring 4.4 [67] have been tested in cultured human pluripotent stem cells together with bexarotene 2.2 and all-trans-retinoic acid.…”

Synthesis and preliminary studies of biological activity of amino derivatives of 4-azatricyclo- [5.2.1.02,6]dec-8-ene-3,5-dione with silicon in the structure

“…Organosilicon chemistry was initiated in 1846 by Ebelman, and since that time, silicon compounds have attracted attention of the scientific community. In recent years, silicon-containing bioactive compounds have been reported [14][15][16][17][18][19][20][21]. The incorporation of silicon into organic compounds can improve biological properties such as selectivity, potency, penetration, pharmacokinetics, and pharmacodynamics.…”

“…The incorporation of silicon into organic compounds can improve biological properties such as selectivity, potency, penetration, pharmacokinetics, and pharmacodynamics. Furthermore, replacement of a carbon atom by a silicon atom in existing drugs is an attractive approach to finding new drug candidates [14][15][16][17][18][19]. Some of organosilicon agents have advanced to clinical studies [20,21].…”