title: 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.
authors: Institut für Anorganische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors: Jennifer B
authors: JB
authors: Bauer
authors: W Peter
authors: WP
authors: Lippert
authors: Steffen
authors: S
authors: Dörrich
authors: David
authors: D
authors: Tebbe
authors: Christian
authors: C
authors: Burschka
authors: Victoria B
authors: VB
authors: Christie
authors: Daniel M
authors: DM
authors: Tams
authors: Andrew P
authors: AP
authors: Henderson
authors: Bridgid A
authors: BA
authors: Murray
authors: Todd B
authors: TB
authors: Marder
authors: Stefan A
authors: SA
authors: Przyborski
authors: Reinhold
authors: R
authors: Tacke
mesh_terms: D000077610:Bexarotene; D002454:Cell Differentiation; D049109:Cell Proliferation; D018360:Crystallography, X-Ray; D006801:Humans; D008968:Molecular Conformation; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D012825:Silicon / Q000737:chemistry*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene; D012825:Silicon