ANALOG STUDIES OF RETINOID GLUCURONIDE ACTIVITY

维甲酸(RA)及其代谢物13-顺式维甲酸已成为 治疗皮肤病的药物。这些代理和 它们的类似物(维甲酸)也引起了相当大的兴趣。 因为它们具有潜在的癌症化学预防作用或 化疗药物。尽管是一类很有前途的化合物，但它们的 有效性受到相对较窄的治疗指数的阻碍 这些材料中的大多数。 天然类维甲酸及其类似物迅速和 广泛新陈代谢。这些代谢物中几乎没有保留有用的生物成分。 活性除13-顺式-视黄酸和视黄酸的O-酰基葡萄糖醛酸苷外， 维甲酰-β-葡萄糖醛酸苷。尤其是这种葡萄糖醛酸苷 建议是一种毒性较低的RA活性代谢物。有趣的是， 初步研究表明O-葡萄糖醛酸苷是合成的重要化合物 维甲酸4-羟基苯基维甲酰胺(4-HPR)也可能代表一种毒性较低的， 母体分子的有效代谢物。然而，它还没有成为现实。 显示了这些O-葡萄糖醛酸苷是活性代谢物还是它们 以适当的速度被水解回母体分子 有用的特性。 这个化学项目的具体目标是：1)合成 大量的RA和4-HPR的O-葡萄糖醛酸苷 评价及其放射性标记形式的制备，以评价 它们的摄取和去向，2)上述稳定类似物的制备 以评估完整形式的葡萄糖醛酸苷是否 唯一有效的代谢物，以及3)确定稳定性和/或 这些类似物对β-葡萄糖苷酸酶的抑制活性。 生物学研究的具体目标将是一个全面的 评估这些葡萄糖醛酸苷及其类似物的能力：1) 对人乳腺癌细胞MCF-7体外生长的影响 预防DMBA诱导的大鼠乳腺转化；3)BE 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发展任何 看起来很有希望的化合物。

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.