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）：全合成提供了一种生产化疗剂的新方法。本研究的目的是合成抗肿瘤药物圆线虫素-26并研究其构效关系。该基金将开发新的方法来全合成有助于治疗癌症转移的圆线虫素。 Strongylophorine-26是一种很有前途的Rho依赖性肿瘤细胞侵袭抑制剂。据观察，STP-26减少肌动蛋白应力纤维，并诱导非极化板状伪足延伸。然而，STP-26从其天然来源的有限可用性阻碍了进一步的机制研究，例如STP-26是否在体内显示抗转移或抗血管生成活性。因此，本申请中提出的研究的直接目标是开发STP-26的合成路线，作为更严格的生物学研究的可靠药物来源。该项目将同时提供结构-活性研究所需的类似物，这些类似物不容易通过天然产物的修饰获得。从我们的合成材料的拟议研究中获得的生物学数据将在短期内导致STP-26的作用机制的阐明，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合成STP-26。这两种途径都受益于使用已知的三环前体，以及高度收敛的计划，其中高级四环和醌前体在后期偶联。这种模块化的方法是有吸引力的模拟合成，因为它允许两个区域的目标，是重要的活动是系统地变化。这两种途径主要在引入内酯的策略方面有所不同。第一条路线的优势是， 反应，关键步骤是巴顿自由基环化反应。第二条路线集中在过渡金属催化的远程C-H活化的新方案。该方法允许使用市售材料香叶基芳樟醇并以更有效的方式引入内酯环。因此，放大合成将是实用的。此外，这种新的C-H激活策略将发现广泛的应用于其他生物活性萜类和类固醇。 STP-26类似物的构效关系（SAR）图谱的阐明将通过与Sloan-Kettering癌症中心的Ting-Chao Chou博士和康奈尔大学威尔医学院的Xin-Yun Huang教授合作完成。我们的合成策略使其方便地获得具有圆线虫骨架的修饰官能团，从而产生具有潜在更大药理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醌环上的不同位置，这是通过修饰天然产物无法轻易实现的。众所周知，醌环上的甲氧基对于良好的活性非常重要。这是否是由于其电子和/或空间效应将是 通过引入一系列给电子或吸电子基团（烷基、OEt、NR 2、卤素、CN等）进行测试。取代甲氧基。此外，内酯环是活性所必需的，可能是因为其对亲核攻击的敏感性。这将通过将内酯环修饰为内酰胺、内半缩醛或其开环羟基酸进行检测。