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病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能和引起维生素a中毒的倾向。然而，RA的o -酰基葡萄糖醛酸代谢物被认为是一种毒性较小的活性物质。合成的类维甲酸N-（4-羟基苯基）维甲酸（4-HPR）显示出一些独特的乳腺癌化学预防活性，进一步降低了毒性和致畸性。我们对4-HPR- o -葡糖苷（4-HPROG）的研究表明，相对于4-HPR，它对dba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，这些葡萄糖醛酸以及视黄酰胺4-HPR在水解回母体类视黄酰胺时是不稳定的，因此不清楚分子的活性形式是什么。我们已经合成了稳定的4-HPR和4- hprog的c -链类似物，用于评估作为乳腺癌化学预防/化疗药物。与4-HPR相比，许多类似物显示出更高的预防dmba诱导肿瘤的效力，并进一步降低毒性。与4-HPR一样，这些类似物与已知的核类视黄醛受体结合较弱，与RA不同，它们以不受类视黄醛受体拮抗剂抑制的方式导致肿瘤细胞凋亡，其作用机制尚不完全清楚。我们建议继续研究的具体目标是：1)基于目前正在进行的化疗/化学预防实验，扩大我们首选类似物（4- hbr、4- hbrcg或4- hbrcglucose）的生产规模；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)开始在第二种（MMTV/ErbB2小鼠）乳腺肿瘤模型中研究所选类似物；4)对所选类似物进行预测致畸研究。5)探讨所选类似物的作用机制问题，重点关注我们观察到的4-HPR和我们的类似物似乎诱导内质网应激。我们将在这里着重于确定这些现象对这些化合物的作用的必要性，以及确定触发这些事件的这些过程上游的分子参与者。公共卫生相关性：尽管最近取得了进展，但乳腺癌相关的发病率和死亡率在美国仍然是一个严重的问题。我们正在开发的4-HPR类似物显示出作为更有效、毒性更低的乳腺癌预防和治疗药物的真正希望。更清楚地了解这些有前途的分子如何发挥作用，将进一步提高我们开发和利用它们的能力。

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. PUBLIC HEALTH RELEVANCE: Despite recent advances, breast cancer-associated morbidity and mortality remains a serious problem in the USA. The analogs of 4-HPR we are developing, show real promise as more effective and less toxic preventive and therapeutic agents for breast cancer. A clearer understanding of how these promising molecules function would further enhance our ability to develop and exploit them.