ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

视黄酸（RA）及其类似物已成为皮肤病药物 和作为潜在的癌症化学预防/化学治疗剂。 作为 类，这些化合物往往共享致畸潜力， 显示维生素A毒性的能力 然而，O-酰基葡糖苷酸 RA的代谢物被认为是毒性较小的活性产物。 合成的类维生素A 4-羟基苯基视黄酰胺（4-HPR）显示出一些 作为乳腺癌化学预防剂的独特理想特征 具有降低的毒性和致畸性。 我们对4-HPR-O的研究 葡萄糖醛酸苷显示其毒性甚至比4-HPR更小，活性更高， 一种乳腺癌化学预防剂 然而，这些葡萄糖醛酸苷是 对水解不稳定。 我们一直在合成稳定的N-和C- 用于评估乳腺癌的RA和4-HPR-O-葡糖苷酸的连接类似物 癌症化学预防/化学治疗活性（CA 49837）。 一些 这些类似物显示出巨大的希望，尽管事实上，他们不 与任何已知的核受体结合良好。 的具体目标 我们的计划是：1）大规模合成我们最有前途的类似物 更详细的体内和体外研究。 具体来说，我们将 完成我们对乳腺肿瘤化学预防活性的评估 和化疗潜力。 类似物对细胞凋亡的影响 细胞培养中的活性、增殖和分化也将 进行评估。 化合物的维生素A活性将使用 大鼠生长测定和诱导大鼠细胞凋亡的能力 也将研究乳腺肿瘤; 2）合成一组有限的 探针机制和代谢的额外稳定C-连接类似物 问题;和3）关键放射性标记的类似物的合成，以促进 代谢研究，并探讨分子作用机制， 这些化合物。

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.