Retinoic acid (RA, 1), an oxidized form of
vitamin A, binds to
retinoic acid receptors (RAR) and
retinoid X receptors (RXR) to regulate gene expression and has important functions such as cell proliferation and differentiation. Synthetic
ligands regarding RAR and RXR have been devised for the treatment of various diseases, particularly promyelocytic
leukemia, but their side effects have led to the development of new, less toxic therapeutic agents.
Fenretinide (4-HPR, 2), an aminophenol derivative of RA, exhibits potent antiproliferative activity without binding to RAR/RXR, but its clinical trial was discontinued due to side effects of impaired dark adaptation. Assuming that the
cyclohexene ring of
4-HPR is the cause of the side effects, methylaminophenol was discovered through structure-activity relationship research, and
p-dodecylaminophenol (p-DDAP, 3), which has no side effects or toxicity and is effective against a wide range of
cancers, was developed. Therefore, we thought that introducing the motif
carboxylic acid found in
retinoids, could potentially enhance the anti-proliferative effects. Introducing chain terminal carboxylic functionality into potent p-alkylaminophenols significantly attenuated antiproliferative potencies, while a similar structural modification of weakly potent p-acylaminophenols enhanced growth inhibitory potencies. However, conversion of the
carboxylic acid moieties to their methyl
esters completely abolished the cell growth inhibitory effects of both series. Insertion of a
carboxylic acid moiety, which is important for binding to RA receptors, abolishes the action of p-alkylaminophenols, but enhances the action of p-acylaminophenols. This suggests that the amido functionality may be important for the growth inhibitory effects of the
carboxylic acids.