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Novel Silicon‐Containing Analogues of the Retinoid Agonist Bexarotene: Syntheses and Biological Effects on Human Pluripotent Stem Cells
Author(s) -
Bauer Jennifer B.,
Lippert W. Peter,
Dörrich Steffen,
Tebbe David,
Burschka Christian,
Christie Victoria B.,
Tams Daniel M.,
Henderson Andrew P.,
Murray Bridgid A.,
Marder Todd B.,
Przyborski Stefan A.,
Tacke Reinhold
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100156
Subject(s) - bexarotene , retinoid x receptor , chemistry , stereochemistry , retinoid , agonist , moiety , hela , induced pluripotent stem cell , retinoic acid , biochemistry , receptor , cell , nuclear receptor , transcription factor , gene , embryonic stem cell
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 SiCH 2 CH 2 Si group in disila‐bexarotene with a SiCH 2 Si 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 HCC(CH 3 ) 2 SiCH 2 Si(CH 3 ) 2 CCH and HCC(CH 3 ) 2 SiOSi(CH 3 ) 2 CCH, 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.