Total Synthesis of Anticancer Agent Strongylophorine-26 and Studies Directed to U

抗癌剂Strongylophorine-26的全合成及针对U的研究

• 批准号: 8500398
• 负责人: Shengping Zheng
• 金额: $ 14.76万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8500398
• 关键词: Acids; Actins; Adhesions; Angiogenesis Inhibitors; Antineoplastic Agents; Biological; Biological Factors; Cancer Center; Cause of Death; Cells; Collaborations; Coupled; Cyclization; Data; Development; Diagnosis; Diterpenes; Electronics; Electrons; Focal Adhesions; Goals; Grant; Hydroxyl Radical; Lactams; Lactones; Lead; Letters; Malignant Neoplasms; Marines; Mediating; Mentors; Methodology; Methods; Modification; Neoplasm Metastasis; New Agents; Organic Synthesis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Porifera; Positioning Attribute; Predisposition; Proteins; Protocols documentation; Quinones; Reaction; Research; Role; Route; Series; Source; Staging; Steroids; Stress Fibers; Structure; Structure-Activity Relationship; Terpenes; Testing; Therapeutic; Time; Transition Elements; Tumor Cell Invasion; Universities; alkyl group; analog; anti-cancer therapeutic; base; career; cell motility; chemical synthesis; chemotherapeutic agent; cytotoxicity test; functional group; in vivo; inhibitor/antagonist; medical schools; neoplastic cell; novel; prevent; professor; rho; rho GTP-Binding Proteins; scale up; tumor

DESCRIPTION (provided by applicant): Total synthesis provides a new way to produce chemotherapeutic agents. The goals of this proposed research are to synthesize anticancer agent strongylophorine-26 and to elucidate its SAR profiles. This grant will develop new methodology to the total syntheses of strongylophorines which are helpful with treating cancer metastasis. Strongylophorine-26 is a promising Rho-dependent inhibitor of tumor cell invasion. It was observed that STP-26 reduces actin stress fibers and induces nonpolarized lamellipodial extensions. However, the limited availability of STP-26 from its natural source has prevented further mechanistic studies, such as whether STP-26 shows antimetastatic or antiangiogenic activity in vivo. Accordingly, an immediate goal of the research proposed in this application is the development of a synthetic route to STP-26, as a reliable source of the drug for more rigorous biological studies. This project will at the same time make available analogs that are required for structure-activity studies, and which are not easily accessible through modification of the natural product. The biological data from the proposed studies of our synthetic materials will in the short term lead to elucidation of the mechanism of action of STP-26 and ultimately to a clearer understanding of Rho mediated anti-metastatic pathways and to new anticancer therapeutics. We propose to develop two independent syntheses of STP-26. Both routes benefit from the use of known tricyclic precursors, and a highly convergent plan in which advanced tetracyclic and quinone precursors are coupled at a late stage. This modular approach is attractive for analog synthesis, because it allows two regions of the target that are important for activity to be systematically varied. The two routes vary mainly with respect to the strategy for introduction of lactone. The first route has the advantage of well-established organic reactions, the key step being a Barton radical cyclization reaction. The second route centers on a new protocol for transition metal catalyzed remote C-H activation. This methodology permits the use of the commercially available material geranyllinalool and the introduction of the lactone ring in a more efficient way. Therefore, a scale-up synthesis will be practical. Furthermore, this novel C-H activation strategy will find broad application to other bioactive terpenoids and steroids. The elucidation of structure-activity relationship (SAR) profiles of analogs of STP-26 will be done through collaboration with Dr. Ting-Chao Chou at Sloan-Kettering Cancer Center and Professor Xin-Yun Huang at Weill Medical College of Cornell University. Our synthetic strategies make it convenient to obtain modified functional groups with the strongylophorine framework, thereby generating structural mimics with potentially greater pharmacological activity and therapeutic potential. Furthermore, our chemical synthesis would facilitate the introduction of substituents into different positions on the quinone ring, which cannot be easily achieved by modification of the natural product. The methoxy group on the quinone ring is known to be important for good activity. Whether this is because of its electronic and/or steric effect will be tested by introducing a series of electron-donating or electron withdrawing groups (alkyl, OEt, NR2, halide, CN etc.) to replace the methoxy group. Moreover, the lactone ring is necessary for activity probably because of its susceptibility to nucleophilic attack. This will be tested by modifying the lactone ring to lactam, lactol, or its seco hydroxyl acid.

描述（由申请人提供）：总合成提供了一种产生化学治疗剂的新方法。这项拟议的研究的目标是合成抗癌剂strongylophorine-26并阐明其SAR谱。该赠款将开发新的方法论，以有助于治疗癌症转移有助于牢固型的总合成。 强酚26是一种有前途的Rho依赖性肿瘤细胞浸润抑制剂。据观察，STP-26可减少肌动蛋白应激纤维并诱导非极化层状叶片延伸。但是，STP-26从自然来源的有限可用性阻止了进一步的机械研究，例如STP-26在体内是否显示抗转移性或抗血管生成活性。因此，在本应用中提出的研究的直接目标是开发了向STP-26的合成途径，这是用于更严格的生物学研究的可靠来源。该项目将同时提供结构活性研究所需的类似物，并且通过修改天然产品不容易访问。在短期内，我们提出的合成材料研究的生物数据将导致STP-26的作用机理，并最终更清楚地了解Rho介导的抗转移途径和新的抗癌疗法。 我们建议开发两个独立的STP-26合成。两种路线都受益于已知的三环前体，以及高度收敛的计划，其中高级四环素和奎因酮前体在后期耦合。这种模块化方法对模拟合成具有吸引力，因为它允许目标的两个区域对活动的系统变化很重要。这两条路线主要在引入内酯的策略方面有所不同。第一条路线具有成熟有机的优势 反应，关键步骤是Barton自由基环化反应。第二个路线以新的转换金属催化远程C-H激活的方案为中心。该方法允许使用市售的材料Geranyllinalool和更有效地引入内酯环。因此，扩大合成将是实际的。此外，这种新型的C-H激活策略将在其他生物活性萜类化合物和类固醇中找到广泛的应用。 STP-26类似物的结构活性关系（SAR）概况将通过与Sloan-Kettering癌症中心的Ting-Chao Chou博士和康奈尔大学Weill医学院的Xin-Yun Huang教授合作来完成。我们的合成策略使得获得具有强层框架的改良官能团变得方便，从而产生具有更大的药理学活性和治疗潜力的结构模拟物。此外，我们的化学合成将有助于将取代基引入奎因酮环上的不同位置，这不能通过修饰天然产物来轻松实现。已知奎因酮环上的甲氧基对良好的活性很重要。这是否是因为其电子和/或空间效应将是 通过引入一系列散液或电子抽出组（烷基，OET，NR2，HALIDE，CN等）进行测试以替代甲氧基。此外，内酯环可能是由于其对亲核攻击的敏感性而需要的。这将通过将内酯环改成乳糖果，乳糖或其SECO羟基来测试。