Chemical Synthesis of Complex Natural Products for Translational Science

项目摘要 用于转化科学的复杂天然产物的化学合成 继续MIRA（R35 GM 118173）研究计划的目标是继续关注化学 用于翻译研究的生物活性分子的合成。MIRA的努力将允许灵活性和稳定性， 使新的研究方向在研究过程中出现。R35的前四年 该计划的成果丰硕，并在高影响力期刊上发表了30篇论文。其中包括17 与临床和生物学研究者合作撰写的手稿。作为我们研究的一部分， 解决有机化学中的关键问题和当代需求的机会，包括不对称 光催化环加成，仿生级联反应和环加成，和化学酶 合成.过去四年的主要成就包括合成脒基罗卡酸酯（ADR）， 高效翻译抑制剂，使用反应性烯三酮合成部分萜类，仿生合成 通过脱芳构化驱动的多环化反应，以及手性离子对的计算研究 使用并行回火（PT）计算。作为MIRA更新项目的一部分，主要研究者 John Porco教授及其同事将继续开发新的合成方法， 进入生物活性类别的天然产物，包括罗卡酸酯、氧杂非那烯酮、meroterpenoids、螺环- PPAP、多环氧杂蒽酮和四氧杂蒽酮、氧杂蒽酮二聚体、蒽烯，以及 吡咯亚氨基醌生物碱。该项目将继续主要侧重于合作研究生物 用作人的药理学疗法的靶分子的性质和作用模式（MoA） 癌症以及病毒、真菌和细菌疾病。预计MIRA计划将允许我们 继续开发复杂天然产品和衍生物的创新合成，并努力 积极地将这些研究与临床和转化研究中的应用相结合。

PROJECT SUMMARY Chemical Synthesis of Complex Natural Products for Translational Science The goals of the continuing MIRA (R35GM118173) research program are to continue focus on chemical syntheses of bioactive molecules for translational studies. The MIRA effort will allow flexibility and stability to enable new research directions that come up during the course of research. The first four years of the R35 program have been highly productive and have led to 30 publications in high impact journals. This includes 17 collaborative manuscripts with clinical and biological investigators. As part of our studies, we have taken opportunities to address key questions and contemporary needs in organic chemistry including asymmetric catalysis of photocycloadditions, biomimetic cascade reactions and cycloadditions, and chemoenzymatic synthesis. Key accomplishments in the past four years include synthesis of amidino rocaglates (ADRs) as highly potent translation inhibitors, synthesis of meroterpenoids using reactive enetriones, biomimetic synthesis of meroterpenoids by dearomatization-driven polycyclization, and computational investigation of chiral ion-pairs using parallel tempering (PT) computation. As part of the MIRA renewal project, the Principal Investigator Professor John Porco and colleagues will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including rocaglates, oxaphenalenones, meroterpenoids, spiro- PPAPs, polycyclic xanthones and tetrahydroxanthones, xanthone dimers, trichothecenes, and pyrroloiminoquinone alkaloids. The project will continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for use as pharmacological therapies for human cancers as well as viral, fungal, and bacterial illnesses. It is anticipated that the MIRA program will allow us to continue development of innovative syntheses of complex natural products and derivatives and work to aggressively interface these studies with applications in clinical and translational research.