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

描述(由申请人提供)：多药耐药(MDR)癌症是人类健康领域一个紧迫且日益严重的问题。由于这些癌症表型对已知化疗药物的治疗反应很差，因此需要新的细胞毒性试剂来对抗它们。海洋生物碱N-甲基威灵酮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多药耐药乳腺癌细胞(MCF-7，IC50=130 nm)显示出强大的细胞毒活性，而且还被证明可以逆转这些细胞株的耐药性，使它们对紫杉醇等传统抗癌药物的敏感性增加100倍。由于从天然来源分离它是一个费时费力的过程，提供的原料很少，所以N-甲基韦林酮C异硫氰酸酯的全合成是一种获得更多这种有效生物活性化合物的有效技术。本文提出了一种新的、简明的制备N-甲基异硫氰酸异硫氰酸酯的方法。该项目将涉及开发一种用于芳基卤化物与邻甲基酚偶联的对映选择性氧化脱芳构化反应。这一新方法将提供获得具有全碳1-四元立体中心的富对映体环己二烯酮产品的途径。通过将这一技术应用于N-甲基韦林酮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，这反过来又将使这种海洋生物碱的制备变得方便。 公共卫生相关性：本文提出的研究描述了生物活性、多药耐药、抗癌天然产品N-甲基韦林酮C异硫氰酸酯的制备。该项目涉及开发一种有效构建复杂有机分子的新反应，这项技术将应用于快速完成上述天然产物。由于N-甲基威灵酮C异硫氰酸酯对有弹性的癌症株显示出强大的疗效，但只有少量的天然药物可用，这些努力将通过提供便捷的途径获得这种稀有化合物用于测试和研究，从而有助于新型化疗药物的发展。

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.