Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes.

摘要: The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding activation three closely related receptor subtypes (RAR alpha, RAR beta, gamma). In order to investigate the role subtypes, we have carried out a chemical synthesis program seek selective for these receptors. We measured affinity using recombinant -beta, -gamma proteins assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified 4-substituted-3-(1-adamantyl)phenyl moiety as new pharmacophore which can replace beta-cyclogeranylidene ring naturally occurring all-trans-retinoic acid. Two series derived from general structures 6-(3-tertioalkylphenyl)-2-naphthoic (series I) 4-[(E)-2-(3-tertioalkylphenyl)propenyl]benzoic II) were developed. particular, obtained gamma derivatives 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic (7) [Ki(RAR alpha) = 6500 nM, Ki(RAR beta) 2480 gamma) 77 nM] 4-[(E)-2-[3-(1-adamantyl)-4-hydroxyphenyl]propenyl]benzoic (19) 1,144 1245 53 nM]. I, presence phenol group, irrespective nature tertioalkyl imparted at least partial selectivity, whereas II, both adamantyl groups is needed confer selectivity. ligands induce differentiation (7, AC50 33 nM; 19, 66 nM). From mixed beta-gamma agonist with potent was selected development topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic (5, CD 271) 1100 Ki-(RAR 34 130 AC50(F9) 37 Finally, weak antagonist assay, 4-[(E)-2-(3-tert-butyl-4-hydroxyphenyl)propenyl]benzoic (15, IC50 700