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

Abstract

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.

• Authors: Rosana Alvarez, M Jesús Vega, Sabrina Kammerer, Aurélie Rossin, Pierre Germain, Hinrich Gronemeyer, Angel R de Lera
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 24 Pg. 6117-22 (Dec 20 2004) ISSN: 0960-894X [Print] England
• PMID: 15546741 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ligands
• Nicotinic Acids
• Receptors, Retinoic Acid
• Retinoid X Receptors
• Alitretinoin
• Tretinoin

Topics

• Alitretinoin
• Hydrophobic and Hydrophilic Interactions
• Ligands
• Models, Molecular
• Molecular Structure
• Nicotinic Acids (chemical synthesis, chemistry, pharmacology)
• Receptors, Retinoic Acid (agonists)
• Retinoid X Receptors (agonists)
• Structure-Activity Relationship
• Tretinoin (chemical synthesis, chemistry, pharmacology)