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：
8264264
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8264264
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. PUBLIC HEALTH RELEVANCE: Our proposed research focuses on the development of new methods to the synthesis of biologically active natural products and mimics which are useful for treating tumor metastasis. Specifically, the goals of this proposed research are to synthesize anticancer agent strongylophorine -26 and to study the structural requirements for its anti-metastatic activity.

描述（申请人提供）：全合成提供了生产化疗药物的新途径。本研究的目标是合成抗癌剂 Strongylophorine-26 并阐明其 SAR 特征。这笔赠款将开发全合成强效碱的新方法，这有助于治疗癌症转移。 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足延伸。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 是否在体内表现出抗转移或抗血管生成活性。因此，本申请提出的研究的直接目标是开发 STP-26 的合成途径，作为更严格的生物学研究的可靠药物来源。该项目同时将提供结构活性研究所需的类似物，而这些类似物通过天然产物的修饰很难获得。我们的合成材料拟议研究的生物学数据将在短期内阐明 STP-26 的作用机制，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。我们建议开发两种独立的 STP-26 合成方法。这两条路线都受益于已知三环前体的使用，以及先进的四环和醌前体在后期耦合的高度收敛计划。这种模块化方法对于模拟合成很有吸引力，因为它允许对活性重要的靶标的两个区域系统地变化。这两条路线的不同主要在于引入内酯的策略。第一条路线的优势在于成熟的有机反应，关键步骤是巴顿自由基环化反应。第二条路线以过渡金属催化远程 C-H 激活的新协议为中心。该方法允许使用市售材料香叶基醛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，这种新颖的 C-H 激活策略将广泛应用于其他生物活性萜类化合物和类固醇。 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 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。我们的合成策略可以方便地获得具有强碱框架的修饰官能团，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，这是通过天然产物的修饰无法轻易实现的。已知醌环上的甲氧基对于良好的活性很重要。这是否是由于其电子和/或空间效应所致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）来取代甲氧基进行测试。此外，内酯环对于活性来说是必需的，可能是因为它对亲核攻击敏感。这将通过将内酯环修饰为内酰胺、内醇或其仲羟基酸来测试。公共健康相关性：我们提出的研究重点是开发合成可用于治疗肿瘤转移的生物活性天然产物和模拟物的新方法。具体来说，本研究的目标是合成抗癌剂强效碱-26并研究其抗转移活性的结构要求。