New Methods for the Synthesis of Biologically Active Peroxides

项目摘要/摘要 虽然天然产生的过氧化青蒿素在抗击疟疾方面发挥了重要作用， 合成过氧物的困难使药物化学家在追求多种类型的 作为候选药物的过氧物。这项研究计划的长期目标是开发新的方法来 过氧化物的合成及其生物活性的研究。初步实验表明，金属- O2的催化反应提供了制备过氧物的新方法，这些反应可以与 区域和立体选择性，以及五元环过氧化物选择性地抗癌细胞。 这些化合物诱导细胞死亡的原因不是细胞凋亡，这是由抗肿瘤药物诱导的常见途径。 抗癌药物，表明非典型的过氧化氢结构导致非典型的活性。以下是具体的 我们将追求以下目标：(1)我们将开发利用氧气进行立体选择性过氧化的新方法；(2)我们将 探索一步合成环状过氧化氢的新方法；以及(3)我们将开发用于合成环状过氧化物的方法 五元环过氧化物的立体选择性合成及生物活性评价。第一个目标是， 我们将扩大初步研究表明，金属催化的O2反应可以用来引入 过氧化官能团立体选择性地转化为有机化合物，包括呋喃，以及那些 化合物可以转化成类似天然产品的结构。第二个目标将检查 有机化合物一步加氧合成环状过氧化氢的新方法 具有多种有效生物活性的一类化合物。第三个目标将完善我们的 了解五元环过氧化氢如何通过铁下垂导致细胞死亡，铁下垂是一种铁依赖的形式 布伦特·斯托克韦尔教授(哥伦比亚大学)发现了细胞死亡。这些研究将在 与斯托克韦尔教授和威廉·卡罗尔教授(纽约大学珀尔穆特癌症中心)合作 Lara Mahal教授(纽约大学化学系)。我们还将评估新的方法，用于 这些过氧化物的立体选择性合成，因为我们已经证明了它的生物活性 取决于立体化学。这项拟议的研究具有创新性，因为它使用了新的金属催化 反应引入过氧化氢官能团，因为它试图解决选择性问题 在文献中没有得到很好的阐述。这项拟议的研究意义重大，因为它将导致新的反应 以及合成具有挑战性的官能团的方法，该官能团是具有有效生物活性的化合物的一部分 活动。生物学研究将具有重要意义，因为它们将为铁下垂提供洞察力。这些 研究与人类健康有关，因为五元环过氧化氢的作用机制 杀死癌细胞的途径与大多数药物遵循的途径不同，这表明过氧化氢可以作为 对许多化疗药物无效的癌症的补充治疗。

Project Summary/Abstract Although the naturally occurring peroxide artemisinin has played a major role in the fight against malaria, the difficulty of synthesizing peroxides has made it challenging for medicinal chemists to pursue many types of peroxides as drug candidates. The long-term objective of this research program is to develop new methods for the synthesis of peroxides and to explore their biological activity. Preliminary experiments indicate that metal- catalyzed reactions of O2 provide new methods to prepare peroxides, that these reactions can occur with regio- and stereoselectivity, and that five-membered ring peroxides are selectively active against cancer cells. The cause of cell death elicited by these compounds is not apoptosis, the common pathway induced by anti- cancer drugs, suggesting that the atypical peroxide structure leads to atypical activity. The following specific aims will be pursued: (1) we will develop new methods for stereoselective peroxidation using O2; (2) we will explore new approaches for the one-step synthesis of cyclic peroxides; and (3) we will develop methods for the stereoselective synthesis of five-membered ring peroxides and evaluate their biological activity. In the first Aim, we will extend preliminary studies indicating that metal-catalyzed reactions of O2 can be used to introduce the peroxide functional group stereoselectively into organic compounds, including furans, and that those compounds can be transformed into structures resembling natural products. The second Aim will examine new methods for the one-step incorporation of O2 into organic compounds for the synthesis of cyclic peroxides, a family of compounds that exhibits diverse and potent biological activity. The third Aim will refine our understanding of how five-membered ring peroxides cause cell death by ferroptosis, an iron-dependent form of cell death discovered by Professor Brent Stockwell (Columbia University). These studies will be performed in collaboration with Professor Stockwell and with Professor William Carroll (NYU Perlmutter Cancer Center) and Professor Lara Mahal (NYU Department of Chemistry). We will also evaluate new methods for the stereoselective synthesis of these peroxides because we have demonstrated that the biological activity depends upon stereochemistry. The proposed research is innovative because it uses new metal-catalyzed reactions to introduce the peroxide functional group, and because it attempts to solve selectivity issues that are not well addressed in the literature. The proposed research is significant because it will lead to new reactions and methods for the synthesis of a challenging functional group that is part of compounds with potent biological activity. The biological studies will be significant because they will provide insight into ferroptosis. These studies are relevant to human health because the mechanism of action by which five-membered ring peroxides kill cancer cells is distinct from the pathways followed by most drugs, suggesting that peroxides could serve as complementary treatments for cancers that are unresponsive to many chemotherapy agents.