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

Alvarez R, Vega MJ, Kammerer S, Rossin A, Germain P, Gronemeyer H, de Lera AR

Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, 36200 Vigo, Spain.

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.

Published 19 November 2004 in Bioorg Med Chem Lett, 14(24): 6117-22.
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