New retinoid chemotypes: 9-cis-Retinoic acid analogs with hydrophobic rings derived from terpenes as selective RAR agonists

A series of 9-cis-retinoic acid analogs modified at the hydrophobic ring with a (bi)cyclohexenyl moiety derived from natural terpenes has been stereoselectively prepared using a Suzuki cross-coupling as key step. Transient transactivation studies indicate that modification of the hydrophobic ring impacts dramatically on RXR-binding and transactivation, with most retinoids being inactive on RXRβ, while preserving their RAR pan-agonist profile. Furthermore, only the RARγ subtype was capable of enantiomeric discrimination with some pairs of enantiomeric terpene-retinoids.

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