ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

维甲酸（RA）及其类似物已成为流行的 皮肤病药物和潜在的癌症 化学预防/化学治疗剂。 作为一类化合物， 材料具有相当的毒性，并且被迅速和广泛地代谢。 这些代谢物中的大多数显示出相对于母体的活性降低 化合物. 然而，RA的O-酰基葡糖苷酸被认为是 一种毒性较小的活性代谢物 合成类维生素A 4- 羟基苯基视黄酰胺显示出一些独特的理想特征， 有毒的乳腺癌化学预防剂。 我们对4-HPR-O的研究 葡萄糖醛酸苷的研究表明，这种葡萄糖醛酸苷的毒性可能更小， 比4-HPR作为乳腺癌化学预防剂更有效。 但这些 葡萄糖醛酸苷相当不稳定。 因此，我们目前正在合成 4-HPR和RA-O-葡糖苷酸的稳定C-葡糖苷酸类似物， 体外和体内乳腺癌的评价 化学预防/化学治疗活性。 所描述的化学计划的具体目标将是：1）完成 更苛刻的，以前提出的类似物的合成 视黄酰基-β-葡糖苷酸; 2）有限的一组新类似物的合成 基于我们迄今为止的结果; 3）放大合成我们更有前途的 类似物;和4）开发分析技术，以评估 关键化合物的代谢和稳定性。 生物学研究的具体目标是：1）完成和 MCF-7人乳腺肿瘤组织中化合物的含量测定报告 2）化合物在DMBA诱导的大鼠乳腺癌模型中的完整评价 肿瘤模型; 3）评估关键化合物的急性毒性;和4）完成 类似物与核视黄酸受体结合能力的研究， 这是否与基因的激动剂/拮抗剂效应相关 MCF-7细胞的转录、抗增殖和 DMBA诱导的乳腺肿瘤。

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.