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
R
Departamento de Química Orgánica, Facultad de Química, Universidade de Vigo, 36200 Vigo, Spain.
Vega
M Jesús
MJ
Kammerer
Sabrina
S
Rossin
Aurélie
A
Germain
Pierre
P
Gronemeyer
Hinrich
H
de Lera
Angel R
AR
D000077556:Alitretinoin; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000819:agonists; D047488:Retinoid X Receptors / Q000819:agonists*; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D008024:Ligands; D009539:Nicotinic Acids; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D000077556:Alitretinoin; D014212:Tretinoin