New Methods for the Synthesis of Biologically Active Peroxides

合成生物活性过氧化物的新方法

基本信息

批准号：
9238248
负责人：
KEITH ALLEN WOERPEL
金额：
$ 30.54万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9238248
关键词：
Achievement Acids Address Adverse effects Antimalarials Antineoplastic Agents Apoptosis Artemisinins Biological Biological Testing Cancer Center Cancerous Cell Death Cells Chemicals Chemistry Clinical Collaborations Development Disease Exhibits Family Fibroblasts Furans Goals Health Human Incidence Iron Lactones Literature Malaria Malignant Neoplasms Malignant neoplasm of ovary Metals Methods Natural Products One-Step dentin bonding system Outcome Parasites Pathway interactions Periodicity Peroxides Pharmaceutical Preparations Play Preparation Reaction Reporting Research Resistance Role Structure Universities cancer cell cancer therapy cell killing chemotherapy cytotoxic drug candidate enantiomer experimental study fight against functional group innovation insight killings novel strategies perhydroxyl radical peroxidation professor programs stereochemistry

Achievement Acids Address Adverse effects Antimalarials Antineoplastic Agents Apoptosis Artemisinins Biological Biological Testing Cancer Center Cancerous Cell Death Cells Chemicals Chemistry Clinical Collaborations Development Disease Exhibits Family Fibroblasts Furans Goals Health Human Incidence Iron Lactones Literature Malaria Malignant Neoplasms Malignant neoplasm of ovary Metals Methods Natural Products One-Step dentin bonding system Outcome Parasites Pathway interactions Periodicity Peroxides Pharmaceutical Preparations Play Preparation Reaction Reporting Research Resistance Role Structure Universities cancer cell cancer therapy cell killing chemotherapy cytotoxic drug candidate enantiomer experimental study fight against functional group innovation insight killings novel strategies perhydroxyl radical peroxidation professor programs stereochemistry

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项目摘要

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.

项目摘要/摘要尽管天然发生的过氧化蒿氨基甲蛋白酶在与疟疾的斗争中发挥了重要作用，但合成过氧化物的困难使药物化学家追求多种类型的过氧化物作为候选药物。该研究计划的长期目标是为过氧化物的合成并探索其生物学活性。初步实验表明金属 O2的催化反应提供了准备过氧化物的新方法，这些反应可能会随着这些反应而发生区域和立体选择性，五元环的过氧化物对癌细胞有选择性地活跃。这些化合物引起的细胞死亡原因不是凋亡，这是抗 - 引起的公共途径癌症药物，表明非典型的过氧化剂结构导致非典型活性。以下特定将追求目标：（1）我们将使用O2开发新的立体选择性过氧化方法；（2）我们会的探索循环过氧化物一步合成的新方法；（3）我们将开发用于五元环的过氧化物的立体选择性合成并评估其生物学活性。在第一个目标中我们将延长初步研究，表明可以使用金属催化的反应来引入过氧化物的功能组刻有其有机化合物，包括Furans，而这些化合物化合物可以转化为类似天然产品的结构。第二个目标将检查将O2一步掺入有机化合物中的新方法，用于合成环状过氧化物，一个表现出多种多样且有效的生物学活性的化合物家族。第三个目标将完善我们的了解五元环的过氧化物如何导致铁铁作用导致细胞死亡，铁依赖性形式的形式 Brent Stockwell教授（哥伦比亚大学）发现的细胞死亡。这些研究将在与Stockwell教授以及William Carroll（NYU Perlmutter癌症中心）和拉拉·马哈尔（Lara Mahal）教授（纽约大学化学系）。我们还将评估新方法这些过氧化物的立体选择性合成，因为我们已经证明了生物学活性取决于立体化学。拟议的研究具有创新性，因为它使用了新的金属催化引入过氧化物功能组的反应，并且因为它试图解决的选择性问题文献中没有很好的解决。拟议的研究很重要，因为它将导致新的反应以及合成一个具有挑战性的功能群的方法，该官能团是具有有效生物学的化合物的一部分活动。生物学研究将是重要的，因为它们将提供对铁铁作用的见解。这些研究与人类健康有关，因为五元环过氧化物的作用机理杀死癌细胞与大多数药物的途径不同，表明过氧化物可以用作对许多化学疗法剂无反应的癌症的互补疗法。