Retinol, also known as Vitamin A, plays a role in vision, immunity, growth, and cellular differentiation. All-trans retinoic acid (RA) is an oxidized form of retinol that binds to retinoic acid receptors (RARs), resulting in modulation of gene expression related to vital physiological processes including cell growth, differentiation, survival, and death. In contrast, the isomeric RA variant, 9-cis retinoic acid, binds to retinoid X receptors (RXRs), which can exist as heterodimers with RARs or other nuclear receptors. Retinoids (synthetic ligands that engage RARs) and rexinoids (RXR-binding compounds) have therapeutic value against a variety of metabolic diseases and cancer, particularly for the treatment of promyelocytic leukemia. Because retinoids, and to a lesser extent rexinoids, exert unwanted side-effects, there is a need to develop new therapeutic agents that are less toxic. “Atypical retinoids” are synthetic analogs that bind and transactivate RARs and have therapeutic promise as anticancer drugs. However, the mechanism of action of these agents is not completely understood. Fenretinide, [N-(4-hydroxyphenyl)retinamide], is an atypical retinoid that has chemopreventative and anti-proliferative properties, but it has side effects that include night blindness and ocular toxicity. Studies have shown p-dodecylaminophenol (DDAP, which contains structural elements of Fenretinide), to be even more potent in suppressing cancer activity in various cancer cell lines. Because DDAP achieves its effects without binding to RARs and RXRs, it might be possible to enhance its anticancer activity by introducing motifs found in retinoids and rexinoids. The current presentation will cover the design, synthesis, and biological evaluation of a series of analogs that explore this possibility.

Examination of aminophenol-containing compounds designed as antiproliferative agents and potential atypical retinoids

2019 Spring National Meeting

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