ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

维甲酸(RA)及其类似物已成为皮肤科药物 并作为潜在的癌症化学预防/化疗药物。作为一名 类，这些化合物倾向于分享致畸潜力和 显示维生素A毒性的能力。然而，O-酰基葡萄糖醛酸苷 RA的代谢产物被认为是一种毒性较低、活性较高的产品。 合成的维甲酸4-羟基苯基维甲酰胺(4-HPR)显示出一些 作为乳腺癌化学预防药物的独特可取特性 毒性和致畸性降低。我们自己对4-HPR-O-的研究 葡萄糖醛酸苷表明它的毒性甚至比4-HPR更低，活性更高 一种乳腺癌的化学预防药物。然而，这些葡萄糖醛酸苷是 不稳定的，不稳定的。我们一直在合成稳定的N-和C- RA和4-HPR-O-葡萄糖醛酸苷的连锁类似物用于乳房评估 癌症化学预防/治疗活性(CA49837)。一个数字 这些类比显示出巨大的前景，尽管事实并非如此 与任何已知的核受体都能很好地结合。的具体目标 我们的计划是：1)大规模合成我们最有前途的模拟产品 以获取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 被评估。化合物将被检查维生素A活性，使用 大鼠生长测定及诱导大鼠细胞凋亡能力的研究 乳房肿瘤也将被研究；2)合成一组有限的 额外稳定的C-连接类似物用于探测机制和代谢 问题；以及3)合成关键的放射性标记类似物，以促进 代谢研究，并探讨其作用的分子机制 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.