RETINOID DESIGN AND SYNTHESIS

类维生素A的设计与合成

基本信息

批准号：
6491802
负责人：
MARCIA I. DAWSON
金额：
$ 25.62万
依托单位：
MOLECULAR MEDICINE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2002-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6491802
关键词：
antineoplastics breast neoplasms chemical structure function drug design /synthesis /production neoplasm /cancer nutrition therapy receptor binding retinoid binding proteins retinoids vitamin analog vitamin receptor vitamin therapy

项目摘要

Retinoids, on interacting with their two nuclear retinoic acid and retinoid X receptor (RAR and RXR) classes, are able to inhibit breast cancer cell growth and proliferation and induce apoptosis (a process of programmed cell death). The pleiotropic effects of retinoids can also cause toxic side effects that will limit patient compliance. Therefore, new, more effective, less toxic retinoids need to be identified. Because of the diversity of the retinoid response which is modulated either directly or indirectly by the three subtypes in each retinoid receptor class and their isoforms, their ability to function as heterodimers, the response element variations in the promoter regions of genes to which the receptors bind, intermediary coactivators or corepressors, and the various receptor distribution patterns that vary with cell type and differentiation state the probability is high that more selective, less toxic retinoids for breast cancer treatment can be discovered, and then optimized. We have identified new classes of retinoids that inhibit breast cancer cell growth, including receptor subtype- selective retinoids, retinoid panagonists that mimic the activity of 9- cis-retinoic acid by binding and transcriptionally activating both RARs and RAXs, and apoptisis-inducing retinoids that act by a mechanism independent of the retinoid receptors. The goals of Project Retinoid Design and Synthesis, are the discovery and lead optimization of (1) potent, less toxic RAR/RXR panagonists; (2) improved RAR subtype-selective retinoids; (3) analogs of RARgamma-selective 6-[3-[(1-adamantyl)-4-hydroxyphenyl]-2- naphthalenecarboxylic acid (AHPN) that induce apoptosis in breast cancer cells but lack binding a affinity to the RARs so that retinoid toxic side effects are reduced; (4) improved retinoids that repress gene activation from AP-1 sites but do not induce transcription from retinoid response elements; and (5) synthesis of sufficient quantities of selected leads for evaluation at the molecular and cellular level and for subsequent evaluation against breast cancer xenograft growth and for pharmacologic/toxicologic studies in animal models. Optimum retinoids will be used as probes for studying the molecular mechanisms of retinoid action against breast cancer. Retinoid design will be guided by the results of these mechanistic studies and molecular assays to determine receptor selectivity for retinoid response element transcriptional activation or AP-1 site-induced transcriptional repression, couple with receptor binding affinity AHPN analog design will employ the parameters of apoptosis and WAF-1 induction, coupled with the absence of retinoid receptor binding or transcriptional activation. Computational analyses will be used to correlate bioassay results with retinoid structure to generate new leads and optimize them, as has been previously accomplished in current Project I by the design and synthesis of novel RXR-selective, RARgamma-selective, and anti-AP-1 retinoids.

类视黄醇与两个核视黄酸和类视黄醇 X 受体（RAR 和 RXR）类，能够抑制乳腺癌细胞生长和增殖并诱导细胞凋亡（a 细胞程序性死亡的过程）。的多效性效应类视黄醇也会引起毒副作用，从而限制患者遵守。因此，新的、更有效、毒性更小的维A酸需要被识别。由于类维生素A的多样性直接或间接调制的响应每个类视黄醇受体类别及其同种型中的三种亚型，它们作为异二聚体（反应元件）发挥作用的能力受体基因启动子区域的变异结合，中间共激活子或辅阻遏物，以及各种受体分布模式随细胞类型和分化状态的可能性很高，选择性更强，更少可以发现用于乳腺癌治疗的有毒视黄醇，并且然后优化。我们已经确定了新的类视黄醇类别抑制乳腺癌细胞生长，包括受体亚型选择性视黄醇，类视黄醇全激动剂，模仿 9- 的活性顺式视黄酸通过结合并转录激活两者 RAR 和 RAX 以及通过机制独立于类视黄醇受体。的目标类维生素A项目的设计和合成，是发现和领导 (1) 有效、毒性较小的 RAR/RXR panagonists 的优化； (2) 改进的 RAR 亚型选择性视黄醇； (3) 类似物 RARγ-选择性 6-[3-[(1-金刚烷基)-4-羟基苯基]-2- 萘甲酸（AHPN）诱导乳腺细胞凋亡癌细胞但缺乏与 RAR 的结合亲和力，因此类视黄醇毒副作用减少； (4) 改进的类维生素A抑制 AP-1 位点的基因激活但不诱导转录来自类维生素A反应元件； (5)合成足够的用于评估分子和细胞水平和随后的乳腺癌评估异种移植生长和药理学/毒理学研究动物模型。最佳视黄醇将用作探针研究类维生素A对乳腺作用的分子机制癌症。类视黄醇设计将以这些结果为指导确定受体的机制研究和分子测定类维生素A反应元件转录激活的选择性或 AP-1 位点诱导的转录抑制，与受体偶联结合亲和力 AHPN 类似物设计将采用以下参数细胞凋亡和 WAF-1 诱导，加上缺乏类视黄醇受体结合或转录激活。计算分析将用于关联生物测定结果具有类维生素A结构来产生新的线索并优化它们，如之前已在当前项目 I 中通过设计完成新型 RXR 选择性、RARgamma 选择性和合成抗 AP-1 类视黄醇。