Analog Studies of 4-HPR and its Glucuronide

描述(申请人提供)：全反式维甲酸(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。作为一类化合物，这些化合物具有致畸潜力和引起维生素A毒性的倾向。然而，RA的O-酰基葡萄糖醛酸代谢物被认为是一种毒性较低的活性物质。合成的维甲酸N-(4-羟基苯基)维甲酰胺(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。我们自己对4-HPR-O-葡萄糖醛酸苷(4-HPROG)的研究表明，相对于4-HPR，它对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，这些葡萄糖醛酸苷和维甲酰胺4-HPR不稳定，不能水解回到母类维甲酸，因此不清楚这些分子的活性形式是什么。我们一直在合成稳定的4-HPR和4-HPROG的C连接类似物，以评价其作为乳腺癌化学预防/化疗药物的价值。其中一些类似物显示，与4-HPR相比，增强了预防DMBA诱导的肿瘤的效力，并进一步降低了毒性。像4-HPR一样，这些类似物与已知的核维甲酸受体结合很弱，并且与维甲酸不同，它们以一种不被维甲酸受体拮抗剂抑制的方式引起肿瘤细胞的凋亡，使得它们的作用机制尚不完全清楚。我们提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，扩大我们首选的类似物(4-HBR、4-HBRCG或4-HBRC葡萄糖)的生产，2)完成对所选类似物在DMBA诱导的大鼠乳腺肿瘤模型中的化学预防评估，3)开始在第二个(MMTV/ErbB2小鼠)乳腺肿瘤模型中对所选类似物进行研究，4)对所选类似物进行预测畸胎学研究(S)，5)探讨所选类似物(S)的作用机制，重点观察到4-HPR及其类似物似乎能诱导内质网应激。我们将在这里重点确定这些现象对于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的上游分子参与者。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的类似物，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前景。更清楚地了解这些有希望的分子是如何发挥作用的，将进一步增强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.