Inspired by Nature: Rapid Syntheses and Applications of Propellane-Type Michael Acceptors and Biomimetic Syntheses of Hitorins

天然产物或其类似物对生物分子如DNA和蛋白质的共价修饰是 目前一些药物的作用机制。这些共价修饰剂的合成，如 螺桨烷型α-亚甲基-γ-内酯的合成方法， 工具箱受天然产物生物合成的启发，我们建议将关键转化推广到 扩大我们的合成工具箱同时，天然产物已成为目前药物的主要来源， 它们的结构多样性。目前市场上大约一半的小分子药物是天然产品或 它们的合成类似物天然产物合成通过提供替代供应而使药物发现受益 天然来源，并通过制造更活跃的类似物。在这个R15提案中，我们的目标是开发合成 螺桨烷型α-亚甲基-γ-内酯的合成受到我们仿生合成hitorins A和B的启发。Hitorins A 和B是从金粟兰（Chloranthus japonicas）中分离得到的， 日本的胃肠道疾病该提案分为三个具体目标。In Aim 1（仿生 hitorins A和B的合成），我们修改了目前的 hitorins A和B的生物合成方案为自由基级联反应。我们的初步结果强烈支持 我们的新提案目的2合成螺桨烷型α-亚甲基-γ-内酯的一般方法 在探索Aim的过程中，发现了螺桨烷型α-亚甲基-γ-内酯的级联反应 1.详细的机制和广泛的合成能力将在目标2中探索。目标3（生物 研究螺桨烷型α-亚甲基-γ-内酯的重点图书馆），我们将与生物学家合作， 筛选我们的针对不同癌细胞系的合成螺桨烷型α-亚甲基-γ-内酯文库。我们 目的是寻找一种先导化合物，以进一步研究该化合物与生物分子之间的相互作用， 癌细胞从拟议的研究中，我们将深入了解有机反应， 基本化学原理。我的本科同事将接受综合培训， 有机化学这项R15赠款也将有利于纽约州立大学奥尔巴尼分校更好的研究环境。

Covalent modifications of biomolecules, such as DNA and proteins, by natural products or their analogs are the mechanism of action of a number of current drugs. The syntheses of these covalent modifiers, such as propellane-type α-methylene-γ-lactones in this proposal, rely on the methodologies in our current synthetic toolbox. Inspired by the biosynthesis of natural products, we propose to generalize the key transformations to enlarge our synthetic toolbox. Meanwhile, natural products have served as the main source of current drugs due to their structural diversity. About one half of current small-molecule drugs on the market are natural products or their synthetic analogs. Natural product synthesis has benefited drug discovery by providing a supply alternative to the natural source, and by making more active analogs. In this R15 proposal, we aim to develop the synthesis of propellane-type α-methylene-γ-lactones inspired by our biomimetic syntheses of hitorins A and B. Hitorins A and B were isolated from the Chloranthus japonicas, a species that was a traditional medicine to treat gastrointestinal disorders in Japan. This proposal is divided into three Specific Aims. In Aim 1 (Biomimetic synthesis of hitorins A and B based on our modified biosynthetic proposal), we modified the current biosynthetic proposal of hitorins A and B into a radical cascade reaction. Our preliminary results strongly support our new proposal. Aim 2 (A general method to synthesize propellane-type α-methylene-γ-lactones): a cascade reaction was found to synthesize propellane-type α-methylene-γ-lactones during our exploration of Aim 1. The detailed mechanism and a broad synthetic capability will be explored in Aim 2. In Aim 3 (Biological studies of a focused library of propellane-type α-methylene-γ-lactones), we will collaborate with biologists to screen our library of synthetic propellane-type α-methylene-γ-lactones against different cancer cell lines. We aim to find a lead compound to further investigate the interaction between that compound and biomolecules in the cancer cells. From the proposed research, we will have an in-depth understanding of organic reactions and fundamental chemical principles. My undergraduate co-workers will receive comprehensive training in synthetic organic chemistry. This R15 grant will also be beneficial to SUNY-Albany for a better research environment.