ANALOG STUDIES OF 4-HPR AND ITS GLUCURONIDE

描述(申请人提供)：维甲酸(RA)及其类似物已作为皮肤病药物和潜在的癌症化学预防/化疗药物出现。作为一类，这些化合物往往具有致畸潜力和表现出维生素A毒性的能力。然而，RA的O-酰基葡萄糖醛酸代谢物被认为是一种毒性较低、活性较高的产品。合成的维甲酸4-羟基苯基维甲酰胺(4-HPR)显示出一些独特的可取的特性，作为乳腺癌的化学预防药物，降低了毒性和致畸性。我们自己对4-HPR-O-葡萄糖醛酸脂的研究表明，作为乳腺癌的化学预防药物，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，用于评价乳腺癌的化学预防/化疗活性(CA49837)。尽管这些类似物不能很好地与任何已知的核受体结合，但它们仍显示出巨大的前景。我们提出的研究计划的具体目的是：1)合成4-HBR的C-连接葡萄糖醛酸苷类似物(4-HBRCG)，并相对于4-HPRCG评价其在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被证明是化疗中最有效的化合物，并且如果像它的母药4-HBR一样，它在降低血视黄醇方面表现出更低的易感性，那么将使用4-HBRCG进行MTD和化学预防研究。然而，如果4-HPRCG被证明是优越的，我们将把我们的注意力集中在对这种类似物的研究上，包括MTD的评估；2)我们最有效的类似物的化学预防/化疗活性的评估；3)评估在4-HPR及其类似物启动细胞凋亡的过程中RAR激活的必要性；4)[~3H]HPR的合成及其用于确定它是否需要4-HPR的代谢才能起作用；以及4-HPR在细胞和/或体内作用的主要靶点的确定；5)我们最有效的类似物(4-HPRCG或4-HBRCG)在组织分布和致畸潜力方面的评估。

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.