ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

类维生素A葡萄糖苷酸活性的模拟研究

• 批准号: 2093476
• 负责人: Robert W Curley
• 金额: $ 14.47万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 1994-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2093476
• 关键词: 13 cis retinoate; MCF7 cell; antineoplastics; benzanthracenes; breast neoplasms; carcinogenesis inhibitor; chemical carcinogenesis; chemical synthesis; cytotoxicity; disease /disorder model; glucuronides; laboratory rat; mammary gland; neoplasm /cancer nutrition therapy; nutrition related tag; radiopharmacology; retinoids

Retinoic acid (RA) and its metabolite 13-cis-retinoic acid have emerged as agents for the treatment of dermatological conditions. These agents and their analogues (retinoids) have also generated considerable interest because of their potential utility as cancer chemopreventive or chemotherapeutic agents. Although a promising class of compounds, their usefulness has been hampered by the relatively narrow therapeutic indices of most of these materials. The natural retinoids, as well as their analogues, are rapidly and extensively metabolized. Few of these metabolites retain useful biological activity with the exception of 13-cis-RA and the O-acyl glucuronide of RA, retinoyl-beta-glucuronide. THis glucuronide in particular has been suggested to be a less toxic, active metabolite of RA. Interestingly, preliminary studies suggest the O-glucuronide of the important synthetic retinoid 4-hydroxyphenylretinamide (4-HPR) also may represent a less toxic, effective metabolite of the parent molecule. However, it has yet to be shown whether these O-glucuronides are active metabolites or whether they are hydrolyzed back to the parent molecule at an appropriate rate to show useful properties. The specific aims of this chemical program are: 1) the synthesis of substantial quantities of the O-glucuronides of RA and 4-HPR for detailed evaluations as well as their preparation in radiolabelled form to evaluate their uptake and fate, 2) the preparation of stable analogues of the above glucuronides to evaluate whether the intact forms of the glucuronides are uniquely effective metabolites, and 3) determine the stability and/or inhibitory activity of the analogues toward beta-glucuronidase. The specific aims of the biological studies will be a comprehensive evaluation of the ability of these glucuronides and analogues to: 1) influence the growth of MCF-7 human breast cancer cells in vitro, 2) prevent DMBA induced mammary gland transformation in rats, and 3) be absorbed and metabolized by both the cells and experimental animals. Should any of these compounds show useful activities in these models for breast cancer, future goals would include further development of any compounds that appear to be promising.

视黄酸（RA）及其代谢物 13-顺-视黄酸已成为 用于治疗皮肤病的药剂。 这些代理和 它们的类似物（类维生素A）也引起了相当大的兴趣 因为它们具有癌症化学预防或预防作用的潜在用途 化疗剂。 虽然是一类很有前途的化合物，但它们 相对狭窄的治疗指数阻碍了其实用性 大多数这些材料。 天然类视黄醇及其类似物正在迅速且广泛地应用。 广泛代谢。 这些代谢物很少保留有用的生物活性 除 13-cis-RA 和 RA 的 O-酰基葡萄糖苷酸外的活性， 视黄酰-β-葡萄糖苷酸。 尤其是葡萄糖醛酸苷 被认为是 RA 毒性较小的活性代谢物。 有趣的是， 初步研究表明重要的合成物O-葡萄糖苷酸 类视黄醇 4-羟基苯基视黄酰胺 (4-HPR) 也可能代表一种毒性较小的、 母体分子的有效代谢物。 然而，这还有待 显示这些 O-葡萄糖醛酸苷是否是活性代谢物或者它们是否 以适当的速率水解回母体分子以显示 有用的属性。 该化学计划的具体目标是：1）合成 大量的 RA 和 4-HPR 的 O-葡萄糖苷酸，用于详细 评估及其以放射性标记形式进行准备以评估 它们的吸收和命运，2) 上述稳定类似物的制备 葡萄糖醛酸苷以评估葡萄糖醛酸苷的完整形式是否是 独特有效的代谢物，3) 确定稳定性和/或 类似物对β-葡萄糖醛酸酶的抑制活性。 生物学研究的具体目标将是全面的 评估这些葡萄糖醛酸苷和类似物的能力：1) 影响MCF-7人乳腺癌细胞的体外生长，2) 预防 DMBA 诱导的大鼠乳腺转化，并且 3) 被细胞和实验动物吸收和代谢。 如果这些化合物中的任何一个在这些模型中显示出有用的活性 乳腺癌，未来的目标将包括进一步开发任何 看起来很有前途的化合物。