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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

基本信息

批准号：
8639584
负责人：
Shengping Zheng
金额：
$ 15.3万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639584
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

项目摘要

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(申请人提供)：全合成提供了一种生产化疗药物的新方法。这项研究的目的是合成抗癌药物Strylophorine-26，并阐明其SAR图谱。这项资助将为全合成有助于治疗癌症转移的Strylophorine开发新的方法学。Strongylophorine-26是一种很有前途的Rho依赖的肿瘤细胞侵袭抑制物。观察到，STP-26减少了肌动蛋白应激纤维，并诱导了非极化的片脂延长。然而，STP-26的天然来源有限，阻碍了进一步的机制研究，例如STP-26在体内是否显示出抗转移或抗血管生成活性。因此，本申请中提出的研究的一个直接目标是开发一条通往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，而这些类似物不容易通过对天然产物的修饰而获得。从我们合成材料的拟议研究中获得的生物学数据将在短期内有助于阐明STP-26的作用机制，最终有助于更清楚地理解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的合成方法。这两条路线都得益于已知的三环前体的使用，以及高级四环和苯二酚前体在后期偶联的高度收敛计划。这种模块化的方法对模拟合成很有吸引力，因为它允许目标的两个区域系统地变化，这两个区域对活动很重要。这两条路线主要在内酯的引入策略方面有所不同。第一条路线具有成熟的有机路线的优势反应，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活化的新方案上。这种方法允许以更有效的方式使用商业上可获得的材料香叶醇和内酯环的引入。因此，放大合成将是可行的。此外，这一新的C-H激活策略将被广泛应用于其他生物活性萜类和甾体化合物。STP-26类似物的构效关系(SAR)谱的阐明将通过与斯隆-凯特琳癌症中心的周廷超博士和康奈尔大学威尔医学院的黄新云教授合作完成。我们的合成策略使我们可以方便地获得具有强碱骨架的修饰官能团，从而生成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到醌环上的不同位置，这是通过对天然产物进行修饰不容易实现的。已知，对苯二酚环上的甲氧基对良好的活性很重要。无论这是因为它的电子和/或空间效应通过引入一系列给电子或吸电子基团(烷基、OEt、NR2、卤化物、CN等)进行测试。以取代甲氧基团。此外，内酯环是活性所必需的，可能是因为它对亲核攻击很敏感。这将通过将内酯环修饰为内酰胺、乳糖醇或其第二羟基酸来进行测试。