New Methods for the Synthesis of Biologically Active Compounds

项目摘要 我们的长期目标是开发新的化学反应，用于合成可用于 就像药一样。我们将利用我们在合成环状过氧化物方面的专业知识，这是一系列天然产品 它们展示了广泛的生物活性，表明它们应用于疟疾、癌症、 以及病毒和细菌感染。在拟议的资助期内，我们将调查我们的假设 引发铁下垂是环状过氧化物的普遍性质，我们将对其效力和代谢进行优化 我们开发的一种环状过氧化氢FINO2的稳定性，它通过一种新的机制启动细胞死亡。的目标是 FINO2是未知的，所以我们将研究像FINO2这样的环状过氧化氢启动程序化细胞的机制 死亡，与布伦特·斯托克韦尔教授(哥伦比亚大学)合作。我们还将开发新的方法 用于合成在许多天然存在的过氧化氢中发现的环过氧化氢结构基元。我们还将 研究了芳香族过氧物的合成，这类结构的合成和反应活性尚未得到报道。 地址。在拟议的资助期内，我们还将延长对缩醛机理的研究 取代反应是天然产物合成和碳水化合物化学中的重要方法。 通过对模型系统的系统研究，我们可以确定影响稳定性和 氧碳正离子的反应性，它是碳水化合物许多反应的中间体， 包括酶反应。我们将确定唾液酸等糖中的羧基如何影响 涉及这些糖的反应的立体选择性。我们将演示远程邻群 作为控制环类和非环类化合物立体选择性的一种手段。拟议的研究 是创新的，因为它解决了结构类型和活性中间体，这些结构类型和活性中间体几乎没有受到关注 在文学作品中。这项拟议的研究具有重要意义，因为它将引领生物制造的新途径。 并将提供对化学和生物过程的更深层次的机理理解。 这些研究与人类健康相关，因为它们可能导致通过独特途径杀死细胞的药物， 导致了各种疾病的新疗法。此外，对中间体的机械理解 参与碳水化合物的反应可能导致设计酶抑制剂的新方法。

Project Summary Our long-term goal is to develop new chemical reactions for the synthesis of compounds that could be used as medicines. We will build upon our expertise in the synthesis of cyclic peroxides, a family of natural products that exhibit a broad range of biological activities, suggesting their application to the treatment of malaria, cancer, and viral and bacterial infections. During the proposed funding period, we will investigate our hypothesis that initiation of ferroptosis is a general property of cyclic peroxides, and we will optimize the potency and metabolic stability of FINO2, a cyclic peroxide we developed that initiates cell death by a new mechanism. The target of FINO2 is unknown so we will study the mechanism by which cyclic peroxides like FINO2 initiate programmed cell death, in collaboration with Professor Brent Stockwell (Columbia University). We will also develop new methods for the synthesis of the cyclic peroxide structural motif found in many naturally occurring peroxides. We will also investigate the synthesis of aromatic peroxides, a structural class whose synthesis and reactivity have not been addressed. In the proposed funding period, we will also extend our investigations of mechanisms of acetal substitution reactions, which are important methods in natural product synthesis and carbohydrate chemistry. Using systematic studies of model systems, we can identify the factors that contribute to the stability and reactivity of oxocarbenium ions, which are intermediates involved in many of the reactions of carbohydrates, including enzymatic reactions. We will determine how the carboxyl group in sugars such as sialic acids influence the stereoselectivity of reactions involving these sugars. We will demonstrate remote neighboring-group participation as a means of controlling stereoselectivity in cyclic and acyclic compounds. The proposed research is innovative because it addresses structural types and reactive intermediates that have received little attention in the literature. The proposed research is significant because it will lead to new pathways for making biologically active compounds and will provide deeper mechanistic understanding of chemical and biological processes. These studies are relevant to human health because they could result in drugs that kill cells by unique pathways, leading to new treatments for various diseases. Furthermore, the mechanistic understanding of intermediates involved in reactions of carbohydrates could lead to new ways of designing enzyme inhibitors.