Chemical Synthesis of Complex Natural Products for Translational Science

项目总结 用于翻译科学的复杂天然产物的化学合成 持续的MIRA(R35GM118173)研究计划的目标是继续专注于化学品 用于翻译研究的生物活性分子的合成。米拉的努力将允许灵活性和稳定性 使研究过程中出现的新研究方向成为可能。R35的头四年 该计划卓有成效，并在影响力较大的期刊上发表了30篇文章。这包括17个 与临床和生物学研究人员合作的手稿。作为我们研究的一部分，我们采取了 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 光环加成、仿生级联反应和环加成反应的催化作用以及化学酶 综合。在过去的四年中取得的主要成就包括合成了氨基岩石酸酯(ADRs)作为 高效翻译抑制剂、活性烯三酮类化合物的合成、仿生合成 脱芳构化多环化合成硫代萜类化合物及其手性离子对的计算研究 使用并行回火(PT)计算。作为米拉重建项目的一部分，首席调查员 John Porco教授和他的同事们将继续开发简明的新的合成方法 进入生物活性类别的天然产品，包括岩石酸盐，恶杂苯丙酮，硫代萜类，螺环- PPAP、多环杂多酮和四氢杂多酮、杂多酮二聚体、三氯乙烯和 吡咯亚氨基醌生物碱。该项目将继续主要强调合作研究生物学 用于人类药物治疗的靶分子的性质和作用方式 癌症以及病毒、真菌和细菌疾病。预计Mira计划将使我们能够 继续开发复杂天然产物和衍生物的创新合成，并致力于 积极地将这些研究与临床和转化性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.