RETINOID DESIGN AND SYNTHESIS

类维生素A的设计与合成

• 批准号: 6598844
• 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
• 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/6598844
• 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

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.

类维生素A，与其两个核维甲酸相互作用， 类维生素A X受体（RAR和RXR）类，能够抑制 乳腺癌细胞生长增殖和诱导凋亡（a 程序性细胞死亡（Programmed Cell Death）。 的多效性 类维生素A也会引起毒副作用， 合规 因此，新的、更有效的、毒性更小的类维生素A 需要被识别。 由于维甲酸的多样性 直接或间接地被调制的响应。 每类视色素受体类别中的三种亚型及其同种型， 它们作为异源二聚体的功能， 受体所针对的基因的启动子区域的变异 结合，中间辅激活子或辅阻遏子，以及各种 受体分布模式随细胞类型而变化， 分化状态的概率高，选择性越强， 可以发现用于乳腺癌治疗的有毒维甲酸， 然后优化。 我们已经确定了新的类维生素A， 抑制乳腺癌细胞生长，包括受体亚型- 选择性类维生素A，类维生素A泛激动剂，模拟9- 顺式视黄酸通过结合和转录激活 RAR和RAX，以及通过一个或多个受体起作用的诱导骨化的类维生素A， 独立于类维生素A受体的机制。 的目标 维甲酸设计与合成项目，是发现和领导 优化（1）有效的、毒性较小的RAR/RXR泛激动剂;（2） 改进的RAR亚型选择性类维生素A;（3） RAR γ-选择性6-[3-[（1-金刚烷基）-4-羟基苯基]-2- 萘甲酸（AHPN）诱导乳腺癌细胞凋亡 但缺乏对RAR的亲和力， 毒副作用减少;（4）改善抑制 从AP-1位点激活基因，但不诱导转录 从类维生素A反应元件;和（5）合成足够的 在分子水平上进行评价的所选电极导线数量， 细胞水平，并用于随后对乳腺癌的评估 异种移植物生长和药理学/毒理学研究 动物模型 最佳类维生素A将用作探针， 研究维甲酸对乳腺癌作用的分子机制 癌 维甲酸的设计将以这些结果为指导 机制研究和分子测定来确定受体 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 类维生素A受体结合或转录激活。 计算分析将用于关联生物测定结果 与维甲酸结构，以产生新的线索，并优化它们， 在本项目I中，已通过设计完成 以及合成新的RXR选择性、RAR γ选择性和 抗AP-1类维生素A。