ANALOG STUDIES OF 4-HPR AND ITS GLUCURONIDE

描述（由申请人提供）：维甲酸（RA）及其类似物已成为皮肤病药物和潜在的癌症化学预防/化疗药物。作为一类化合物，这些化合物往往具有致畸潜能和显示维生素a毒性的能力。然而，RA的o -酰基葡萄糖醛酸代谢产物被认为是一种毒性较小的活性产物。合成的类维甲酸4-羟基苯基维甲酸（4-HPR）具有降低毒性和致畸性的乳腺癌化学预防剂的一些独特的理想特性。我们自己对4-HPR- o -葡糖苷的研究表明，作为乳腺癌的化学预防手段，它的毒性更小，而且比4-HPR更有效。然而，这些葡萄糖醛酸对水解是不稳定的。我们已经合成了稳定的c -链4- hpr - o -葡萄糖醛酸酯类似物，用于评估乳腺癌化学预防/化疗活性（CA49837）。尽管许多类似物不能很好地与任何已知的核受体结合，但它们仍显示出巨大的希望。我们提出的研究计划的具体目的是：1)合成4-HBR的c -链葡萄糖醛酸类似物（4-HBRCG），并评估其相对于4-HPRCG在dmba诱导的乳腺肿瘤化疗中的疗效，后者是我们在化学预防方面最有效的类似物。如果4-HBRCG被证明是化疗中最活跃的化合物，并且与其母药4-HBR一样，在降低血液视黄醇方面表现出更低的倾向性，那么将使用4-HBRCG进行MTD和化学预防研究。然而，如果4- HPRCG被证明具有优势，我们将把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) [3H]HPR的合成及其用于确定4-HPR是否需要代谢才能起作用；以及在细胞和/或体内鉴定4-HPR作用的主要靶点；5)评估我们最有效的类似物（4- hprcg或4- HBRCG）在组织分布和致畸潜能方面的作用。

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.