Proposal for the Enantioselective Total Synthesis of N-Methylwelwitindolinone C I

描述（由申请人提供）：多药耐药（MDR）癌代表了人类健康领域的一个紧迫和日益严重的问题。由于这些癌症表型对已知化疗剂的治疗反应较差，因此需要新的细胞毒性试剂来对抗它们。海洋生物碱N-甲基维吲哚啉酮C异硫氰酸酯很好地解决了这一问题。这种天然产物不仅对MDR乳腺癌细胞（MCF-7，IC 50 =130 nM）显示出有效的细胞毒活性，而且还显示出逆转这些细胞系的耐药能力，使它们对传统癌症药物（如紫杉醇）的敏感性增加100倍。由于其从天然来源中分离是一个艰苦的过程，提供很少的材料，N-甲基维吲哚啉酮C异硫氰酸酯的全合成准备作为一种有效的技术，以获得额外的量，这种有效的生物活性化合物。本文提出的研究描述了一种新的，简洁的方法对N-甲基welwitindolinone C异硫氰酸酯的制备。该项目将涉及一个对映体选择性的氧化脱芳构化反应的芳基卤与邻羧基苯酚偶联的发展。这种新方法将提供对映体富集的环己二烯酮产品轴承全碳1-季立体中心。通过将该技术应用于N-甲基维吲哚啉酮C异硫氰酸酯的合成，将有可能快速构建天然产物的复杂四环碳支架，这反过来将允许有利地制备这种海洋生物碱。 公共卫生相关性：本文提出的研究描述了被称为N-甲基维吲哚啉酮C异硫氰酸酯的生物活性、多药耐药性、抗癌天然产物的制备。该项目涉及开发一种用于有效构建复杂有机分子的新型反应，该技术将用于快速完成上述天然产物。因为N-甲基维吲哚啉酮C异硫氰酸酯已经显示出对弹性癌细胞系的有效功效，但仅以很少的量天然可用，这些努力将通过提供对这种稀缺化合物的便利途径来帮助新型化学治疗剂的发展以用于测试和研究.

DESCRIPTION (provided by applicant): Multiple drug resistant (MDR) carcinomas represent an urgent and growing problem in the field of human health. Because these cancer phenotypes respond poorly to treatment with known chemotherapeutic agents, there exists a need for novel cytotoxic reagents to combat them. The marine alkaloid N-methylwelwitindolinone C isothiocyanate is well poised to address this situation. Not only has this natural product displayed potent cytotoxic activity against MDR breast cancer cells (MCF-7, IC50=130 nM), but it has also been shown to reverse the drug resistant capacity of these cell lines, making them up to one-hundred fold more susceptible to conventional cancer drugs such as taxol. Because its isolation from natural sources is a painstaking process that affords little material, the total synthesis of N-methylwelwitindolinone C isothiocyanate is poised as an effective technique to access additional quantities of this potent bioactive compound. The research proposed herein describes a novel, concise approach toward the preparation of N- methylwelwitindolinone C isothiocyanate. The project will involve the development of an enantioselective oxidative dearomatization reaction for the coupling of aryl halides with ortho-carboxy phenols. This new method will provide access to enantioenriched cyclohexadienone products bearing all-carbon 1-quaternary stereocenters. By applying this technique to the synthesis of the N-methylwelwitindolinone C isothiocyanate it will be possible to rapidly construct the complex tetracyclic carbon scaffold of the natural product, which will in turn allow expedient preparation of this marine alkaloid. PUBLIC HEALTH RELEVANCE: The research proposed herein describes the preparation of the bioactive, multi-drug resistant, cancer fighting natural product known as N-methylwelwitindolinone C isothiocyanate. The project involves the development of a novel reaction for the efficient construction of complicated organic molecules, a technique that will be applied to the rapid completion of the aforementioned natural product. Because N- methylwelwitindolinone C isothiocyanate has displayed potent efficacy against resilient cancer lines, but is only naturally available in sparingly small amounts, these efforts will aid in the evolution of novel chemotherapeutic agents by affording expedient access to this scarce compound for testing and study.