9-cis-retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists

Rosana Alvarez (1) , M. Jesús Vega (1) , Sabrina Kammerer (2) , Aurélie Rossin (2) , Pierre Germain (2) , Hinrich Gronemeyer (2) , Angel R. de Lera (1)

1 Universidade de Vigo
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Biochimie, Biologie Moléculaire

Rosana Alvarez, M. Jesús Vega, Sabrina Kammerer, Aurélie Rossin, Pierre Germain, et al.. 9-cis-retinoic acid analogues with bulky hydrophobic rings: new RXR-selective agonists. Bioorganic and Medicinal Chemistry Letters, 2004, 14 (24), pp.6117-6122. ⟨10.1016/j.bmcl.2004.08.072⟩. ⟨hal-04122966⟩