ANALOG STUDIES OF 4-HPR AND ITS GLUCURONIDE

描述（由申请人提供）：视黄酸（RA）及其类似物已成为皮肤病药物和潜在的癌症化学预防/化学治疗药物。作为一类，这些化合物往往具有致畸潜力和显示维生素A毒性的能力。然而，RA的O-酰基葡糖苷酸代谢产物被认为是一种毒性较低的活性产物。合成类维生素A 4-羟基苯基视黄酰胺（4-HPR）显示出一些独特的理想功能，作为乳腺癌化学预防剂，具有降低的毒性和致畸性。我们自己对4-HPR-O-葡糖苷酸的研究表明，作为乳腺癌的化学预防剂，它的毒性甚至比4-HPR更低，活性更高。然而，这些葡萄糖醛酸苷对水解不稳定。我们一直在合成4-HPR-O-葡糖苷酸的稳定C-连接类似物，用于评价乳腺癌化学预防/化疗活性（CA 49837）。尽管这些类似物不能很好地与任何已知的核受体结合，但它们中的一些显示出很大的前景。我们提出的研究计划的具体目标是：1）合成4-HBR的C-连接葡糖苷酸类似物（4-HBRCG），并评价其相对于4-HPRCG在DMBA诱导的乳腺肿瘤化疗中的疗效，后者代表我们在化学预防中最有效的类似物。如果4-HBRCG被证明是化疗中最具活性的化合物，并且如果像其母体药物4-HBR一样，它在降低血液视黄醇方面表现出降低的倾向，则将使用4-HBRCG进行MTD和化学预防研究。然而，如果4- HPRCG被证明是上级的，我们将把我们的注意力集中在这种类似物的研究上，包括MTD评估; 2）评估我们最有效的类似物的化学预防/化学治疗活性; 3）评估RAR激活在4-HPR及其类似物引发细胞凋亡中的必要性; 4）[3 H]HPR的合成及其在确定4-HPR的代谢是否是其发挥作用所必需的方面的用途;以及4-HPR在细胞和/或体内作用的主要靶标的鉴定; 5）评估我们最有效的类似物（4-HPRCG或4- HBRCG）的组织分布和致畸潜力。

DESCRIPTION (provided by applicant): 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-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 chemopreventive. 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-induced 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.