Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds tend to share teratogenic potential and the ability to show vitamin A toxicity. However, the O-acyl glucuronide metabolite of RA has been suggested to be a less toxic, active product. The synthetic retinoid 4-hydroxphenylretinamide (4-HPR) shows some uniquely desirable features as a breast cancer chemopreventive agent with reduced toxicity and teratogenicity. Our own studies with 4-HPR-O- glucuronide show it to be even less toxic and more active than 4-HPR as a breast cancer chemopreventive. However, these glucuronides are unstable toward hydrolysis. We have been synthesizing stable N- and C- linked analogs of RA and 4-HPR-O-glucuronides for evaluation of breast cancer chemopreventive/chemotherapeutic activity (CA49837). A number of these analogs show great promise despite the fact that they do not bind well to any of the known nuclear receptors.
The specific aims of our program are: 1) Large-scale synthesis of our most promising analog for more detailed in vivo and in vitro studies. Specifically, we will complete our assessment of the mammary tumor chemopreventive activity and chemotherapeutic potential. The impact of analogs on apoptotic activity, proliferation, and differentiation in cell culture will also be assessed. Compounds will be examined for vitamin A activity using a rat growth assay, and ability to induce apoptosis in cells in rat mammary tumors will also be studied; 2) Synthesis of a limited set of additional stable C-linked analogs to probe mechanism and metabolism issues; and 3) Synthesis of critical radiolabelled analogs to facilitate metabolism studies and to probe the molecular mechanism of action of these compounds.
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