9-cis-Retinoic acid analogues with bulky hydrophobic rings: New RXR-selective agonists
Stille cross-coupling of aryltriflates 10 and dienylstannane 11, oxidation and Horner-Wadsworth-Emmons reaction afforded stereoselectively retinoates 15. Saponification provided the carboxylic acids 8a and 8b, retinoids that incorporate a bulky hydrophobic ring while preserving the 9-cis-geometry of the parent system. In contrast to the pan-RAR/RXR agonistic profile of the lower homologue of 8a, compound 7 (LG100567), retinoids 8 showed selective binding and transactivation of RXR, devoid of significant RAR activation. In PLB985 leukemia cells that require RXR agonists for differentiation compounds 8 induced maturation in the presence of the RAR-selective pan-agonist TTNPB; this effect was blocked by an RXR-selective antagonist.
Alvarez, Rosana,Vega, M. Jesús,Kammerer, Sabrina,Rossin, Aurélie,Germain, Pierre,Gronemeyer, Hinrich,De Lera, Angel R.
p. 6117 - 6122
(2007/10/03)
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