Analog Studies of 4-HPR and its Glucuronide

描述（由申请人提供）：全反式维甲酸（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，这些化合物具有致畸潜力和导致维生素A毒性的倾向。然而，RA的O-酰基葡糖苷酸代谢物被认为是一种毒性较低的活性物质。合成类维生素A N-（4-羟基苯基）视黄酰胺（4-HPR）作为乳腺癌化学预防剂显示出一些独特的活性，并进一步降低毒性和致畸性。我们自己对4-HPR-O-葡糖苷酸（4-HPROG）的研究表明，相对于4-HPR，4-HPROG对DMBA诱导的大鼠乳腺肿瘤具有更低的毒性，更有效的预防和治疗作用。然而，这些葡萄糖醛酸苷以及视黄酰胺4-HPR对于水解回母体类维生素A是不稳定的，使得不清楚分子的活性形式是什么。我们已经合成了4-HPR和4-HPROG的稳定的C-连接的类似物，用于评估作为乳腺癌化学预防/化学治疗剂。许多这些类似物显示出增加的预防DMBA诱导的肿瘤的效力和相对于4-HPR进一步降低的毒性。与4-HPR一样，这些类似物与已知的核类视色素受体弱结合，并且与RA不同，以不被类视色素受体拮抗剂抑制的方式引起肿瘤细胞凋亡，使其作用机制不完全清楚。我们建议继续研究的具体目标是：1）扩大我们首选类似物的生产规模（4-HBR、4-HBRCG或4-HBRC葡萄糖），2）在DMBA诱导的大鼠乳腺肿瘤模型中完成所选类似物的化学预防评估，3）在第二次化疗/化学预防实验中开始所选类似物的研究。（MMTV/ErbB2小鼠）乳腺肿瘤模型，4）进行所选类似物的预测性畸形学研究，和5）探索所选类似物的作用机制问题，重点是我们观察到的4-HPR和我们的类似物似乎诱导ER应激。我们将在这里集中建立这些现象的必要性，这些化合物的行动，以及确定分子球员上游的这些过程中触发这些事件。

DESCRIPTION (provided by applicant): All-trans Retinoic acid (RA) and its analogs have emerged as dermatological agents and as potential cancer chemopreventive/chemotherapeutic agents. As a class, these compounds share teratogenic potential and the tendency to cause vitamin A toxicities. However, the O-acyl glucuronide metabolite of RA has been suggested to be a less toxic, active material. The synthetic retinoid N-(4-hydroxyphenyl) retinamide (4-HPR) shows some unique activity as a breast cancer chemopreventive with further reduced toxicity and teratogenicity. Our own studies with 4-HPR-O-glucuronide (4-HPROG) have shown it to be an even less toxic, more effective preventive and therapeutic for DMBA-induced rat mammary tumors relative to 4-HPR. However, these glucuronides as well as the retinamide 4-HPR are unstable to hydrolysis back to the parent retinoid making it unclear what the active forms of the molecules are. We have been synthesizing stable C-linked analogs of 4- HPR and 4-HPROG for evaluation as breast cancer chemopreventive/chemotherapeutic agents. A number of these analogs show increased potency preventing DMBA-induced tumors and further reduced toxicity relative to 4-HPR. Like 4-HPR, these analogs bind weakly to the known nuclear retinoid receptors and, unlike RA, cause apoptosis in tumor cells in a manner that is not inhibited by retinoid receptor antagonists, leaving their mechanism of action incompletely understood. The specific aims of our proposed continued research are: 1) to scale up production of our preferred analog (4-HBR, 4-HBRCG, or 4-HBRCglucose) based on a current chemotherapy/chemoprevention experiment underway, 2) to complete chemoprevention evaluation of the chosen analog in the DMBA-induced rat mammary tumor model, 3) to begin study of the chosen analog in a second (MMTV/ErbB2 mouse) mammary tumor model, 4) to conduct predictive teratology studies of the chosen analog(s), and 5) to explore mechanism of action issues with the chosen analog(s) focusing on our observations that 4-HPR and our analogs appear to induce ER stress. We will focus here on establishing the necessity of these phenomena for the actions of these compounds as well as determining molecular players upstream of these processes which trigger these events.