ANALOG STUDIES OF 4-HPR AND ITS GLUCURONIDE

维甲酸(RA)及其类似物已成为皮肤科药物和潜在的癌症 化学预防/化疗药物。作为一类，这些化合物往往具有致畸潜力。 以及显示维生素A毒性的能力。然而，RA的O-锥状葡萄糖醛酸代谢物已被 建议是一种毒性较小、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 作为乳腺癌化学预防药物的一些独特的可取特征，具有降低毒性和 致畸性。我们自己对4-HPR-O-葡萄糖醛酸脂的研究表明，它的毒性更低，活性更高 4-hpr可作为乳腺癌的预防药物。然而，这些葡萄糖醛酸苷对水解是不稳定的。我们 一直在合成稳定的C-连接的4-HPR-O-葡萄糖醛酸苷类似物，用于乳腺癌的评估 化学预防/化疗活性(CA49837)。其中一些类比显示出很大的前景 尽管它们不能很好地与任何已知的核受体结合。我们的具体目标是 建议的研究计划是：1)合成4-HBR的C-连接的葡萄糖醛酸苷类似物(4-HBRCG)和 对照4-HPRCG对DMBA诱导的乳腺肿瘤化疗的疗效评价 后者代表了我们在化学预防方面最有效的类似物。如果4-HBRCG被证明是最 化疗中的活性化合物，如果像它的母药4-HBr一样，它在减少 血视黄醇，然后MTD和化学预防研究将用4-HBRCG进行。然而，如有4- HPRCG证明是优越的，我们将专注于这种模拟的研究，包括MTD评估；2) 评估我们最有效的类似物的化学预防/化疗活性；3)评估 RAR激活在4-HPR及其类似物启动细胞凋亡中的必要性；4)[~3H]HPR的合成 用它来确定是否需要4-hpr的代谢才能起作用；以及鉴定初级 4-HPR在细胞和/或体内作用的靶点；5)对我们最有效的类似物(4-HPRCG或4-HPRCG)的评估 HBRCG)关于组织分布和致畸潜力

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-awl glucuronide metabolite of RA has been suggested to be a less toxic, active product. The synthetic retinoid 4-hydroxyphenylretinamide (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 ehemopreentive. However, these glucuronides are unstable toward hydrolysis. We have been synthesizing stable C-linked analogs of 4-HPR-O-glucuronide 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 proposed research program are: 1) synthesis of the C-linked glucuronide analog of 4-HBR (4-HBRCG) and evaluation of its efficacy in chemotherapy of DMBA-indueed mammary tumors relative to 4-HPRCG, the latter of which represents our most effective analog in chemoprevention. If 4-HBRCG proves to be the most active compound in chemotherapy, and if like its parent drug, 4-HBR, it shows reduced liability in reducing blood retinol, then MTD and chemoprevention studies will be performed with 4-HBRCG. if however, 4- HPRCG proves superior, we will focus our attention on studies of this analog, including MTD evaluation; 2) Evaluation of the chemopreventive/chemotherapeutic activity of our most potent analog; 3) evaluate the necessity for RAR activation in the initiation of apoptosis by 4-HPR and its analogs; 4) synthesis of [3H]HPR and its use to determine whether metabolism of 4-HPR is needed for it to act; and identification of the primary target of 4-HPR action in cells and/or in vivo; 5) evaluation of our most potent analog (4-HPRCG or 4- HBRCG) with regard to tissue distribution and teratogenic potential