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

描述（由申请人提供）：全合成提供了一种生产化疗药物的新方法。本研究的目的是合成抗癌药物strongylophori -26并阐明其SAR谱。这项资助将发展新的方法，以全面合成圆形磷素，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。观察到STP-26减少肌动蛋白应力纤维，诱导非极化板足延伸。然而，天然来源STP-26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的合成途径，作为更严格的生物学研究的可靠药物来源。同时，该项目将提供结构活性研究所需的类似物，这些类似物不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阐明STP-26的作用机制，最终更清楚地了解Rho介导的抗转移途径和新的抗癌治疗方法。我们建议开发两种独立的STP-26合成方法。这两种途径都受益于使用已知的三环前体，以及一个高度收敛的计划，其中先进的四环和醌前体在后期耦合。这种模块化方法对模拟合成很有吸引力，因为它允许对活动很重要的目标的两个区域系统地变化。这两种途径主要在引入内酯的战略方面有所不同。第一条路线的优势是建立良好的有机

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.