Retinoic acid (RA) and its analogues have emerged as popular dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class of compounds, these materials are fairly toxic and are rapidly and extensively metabolized. Most of these metabolites show reduced activity relative to the parent compound. However, the O-acyl glucuronide of RA has been suggested to be a less toxic, active metabolite. The synthetic retinoid 4- hydroxyphenylretinamide shows some uniquely desirable features as a less toxic breast cancer chemopreventive agent. Our own studies with 4-HPR-O- glucuronide have suggested this glucuronide may be even less toxic and more active than 4-HPR as a breast cancer chemopreventive. However, these glucuronides are reasonably unstable. Thus we are currently synthesizing stable C-glucuronide analogues of 4-HPR and RA-O-glucuronides for evaluation of both in vitro and in vivo breast cancer chemopreventive/chemotherapeutic activity.
The specific aims of the described chemical program will be: 1) completing the synthesis of the more demanding, previously-proposed analogues of retinoyl-beta-glucuronide; 2) synthesis of a limited set of new analogues based on our results to date; 3) scale-up synthesis of our more promising analogues; and 4) development of analytical techniques to assess metabolism and stability of key compounds.
The specific aims of the biological studies will be to: 1) complete and report on assay of the compounds in the MCF-7 human breast tumor tissue model; 2) complete evaluation of compounds in the DMBA-induced rat mammary tumor model; 3) assess acute toxicity of key compounds; and 4) complete studies of analogue ability to bind to nuclear retinoic acid receptors and whether this correlates with agonist/antagonist effects on gene transcription, antiproliferation of MCF-7 cells and chemoprevention of DMBA-induced mammary tumors.
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