Dr. Robert W. Curley, Jr., Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University; 614-292-7628 (voice); 614-292-2435 (fax);
curley.1@osu.edu (email)

Retinoic acid is a metabolite of vitamin A (retinol) which is essential for growth and epithelial tissue differentiation in mammals and appears to function primarily by interacting with nuclear receptor proteins thereby influencing gene expression. As a result, it and its analogs have generated much interest for development as possible cancer chemopreventive agents. Unfortunately, the use of retinoic acid and many of its analogs has been limited by its toxicity, including a profound ability to cause fetal malformations. Thus, much effort has been spent attempting to find safer, more effective retinoids.

Retinoic acid is rapidly matabolized and one of its metabolites, the relatively unstable glucuronic acid conjugate of retinoic acid, has been suggested to be an active, less toxic metabolite of the parent retinoid. We have been engaged in a lengthy process of designing and synthesizing stable analogs of these unstable metabolites of retinoic acid and its analogs in efforts to determine if these metabolites can function as cancer chemopreventive agents when structurally intact. Many of these analogs are stable, effective as cancer chemopreventive agents, show low toxicity, and do not appear to interact with the nuclear receptors thought to mediate retinoid action. Our efforts in the design, synthesis, and
bioactivity evaluation of these compounds will be described.