Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as potent and selective retinoic acid receptor α agonists
Section snippets
Chemistry
Naphthalenyl and benzopyranyl-pyrrolyl derivatives (11 and 12) were synthesized by the method of Scheme 1. The carbaldehydes (4 and 5), which were prepared by the reported method,4b were treated with vinyl Grignard reagent and oxidized with manganese(IV) oxide (activated) to afford enone derivatives (6 and 7). The enone derivatives (6 and 7) were coupled with methyl 4-formylbenzoate (8) to give the diketones (9 and 10). These derivatives (9 and 10) were treated with ammonium acetate to afford
Results and Discussion
The subtype-selective competitive binding and transactivation data are summarized in Table 1. The 5,8-dimethylnaphthalene derivative 11a did not show affinity for RARβ or RARγ, whereas it has moderate binding affinity for RARα. This compound (11a) is 3-fold less potent at RARα than ATRA, but was 250 and 2000-fold less potent at RARβ and RARγ, respectively. The mono 8-methyl derivative (11b) is less potent than the 5,8-dimethylnaphthalene derivative (11a) in transactivation activity for RARα.
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