ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

维甲酸(RA)及其类似物已成为流行药物 皮肤病药物和潜在的癌症 化学预防/化疗药物。作为一类化合物，这些 物质是相当有毒的，而且代谢迅速且广泛。 这些代谢物中的大多数表现出相对于母体的活性降低。 化合物。然而，维甲酸的O-酰基葡萄糖醛酸苷被建议为 一种毒性较小的活性代谢物。合成的维甲酸4- 羟基苯基维甲酰胺表现出一些独特的可取特征 有毒的乳腺癌化学预防制剂。我们自己对4-HPR-O-的研究 葡萄糖醛酸苷暗示这种葡萄糖醛酸苷的毒性可能更低 作为乳腺癌的化学预防，比4-HPR更有活性。然而，这些 葡萄糖醛酸苷是相当不稳定的。因此，我们目前正在合成 4-HPR和RA-O-葡萄糖醛酸苷的稳定C-葡萄糖醛酸苷类似物 乳腺癌的体内外评价 化学预防/化学治疗活性。 所描述的化学计划的具体目标是：1)完成 合成要求更高的、先前提出的类似物 维甲酰-β-葡萄糖醛酸苷；2)一组有限的新类似物的合成 基于我们到目前为止的结果；3)放大合成更有希望的 类似物；以及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将是：1)完成和 MCF-7人乳腺肿瘤组织中化合物的检测报告 模型；2)DMBA诱导的大鼠乳腺中化合物的完整评价 肿瘤模型；3)评估关键化合物的急性毒性；以及4)完全 类似物与核维甲酸受体结合能力的研究 这是否与基因上的激动剂/拮抗剂效应有关 MCF-7细胞的转录、抗增殖及化学预防 DMBA诱发的乳腺肿瘤。

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.