RETINOID DESIGN AND SYNTHESIS

类维甲酸与其两种核维甲酸和维甲酸相互作用 维甲酸X受体(RAR和RXR)类，能够抑制 乳腺癌细胞的生长和增殖并诱导细胞凋亡(a 程序性细胞死亡的过程)。的多效性效应 类维A酸还会引起毒副作用，限制患者的治疗 合规性。因此，新的，更有效，毒性更低的维甲酸 需要确认身份。因为维甲酸的多样性 直接或间接由 每一类维甲酸受体的三个亚型及其亚型， 它们作为异源二聚体发挥作用的能力，即响应元件 受体所在基因启动子区域的变异 结合、中间共激活因子或辅助抑制因子，以及各种 受体的分布模式因细胞类型和 分化状态的概率高，即选择越多，选择越少 可以发现用于乳腺癌治疗的有毒维甲酸，以及 然后进行优化。我们已经确定了新的维甲酸类化合物 抑制乳腺癌细胞生长，包括受体亚型- 选择性维甲酸，类维A酸类泛素激动剂，模拟9- 通过结合和转录激活顺式维甲酸 RAR和RAX，以及诱导细胞凋亡的维甲酸，它们通过 不依赖于维甲酸受体的机制。的目标 维甲酸设计和合成项目，是发现和领导 (1)有效、低毒的RAR/RXR激动剂的优化；(2) 改进的RAR亚型选择性维甲酸；(3)类似物 稀有伽马选择性6-[3-[(1-金刚烷基)-4-羟基苯基]-2- 诱导乳腺细胞凋亡的萘甲酸(AHPN) 但癌细胞缺乏与RARs的亲和力，因此类维甲酸 毒副作用减少；(4)改进的维甲酸抑制 AP-1位点的基因激活，但不能诱导转录 从类维A酸类反应元件；和(5)合成足够的 选定的引线数量在分子和 细胞水平和随后对乳腺癌的评估 异种移植生长及药理学/毒理学研究 动物模型。最佳的维甲酸将被用作探针 维甲酸抗乳腺作用的分子机制研究 癌症。维甲酸的设计将以这些结果为指导 确定受体的机理研究和分子分析 视黄醇反应元件转录激活的选择性或 AP-1结合受体诱导转录抑制 结合亲和力AHPN模拟设计将采用以下参数 细胞凋亡和WAF-1的诱导，加上缺乏 维甲酸受体结合或转录激活。 计算分析将用于关联生物化验结果。 具有维甲酸结构，以产生新的线索并进行优化，如 已在当前项目I中通过设计实现 并合成了新型RXR选择性、RAR伽马选择性和 抗AP-1类维甲酸。

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.