Mechanism of Formation of Polysulfane Anticancer Agents

聚硫烷抗癌剂的形成机理

• 批准号: 7059750
• 负责人: ALEXANDER GREER
• 金额: $ 11.63万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059750
• 关键词: antineoplastics; biological products; biomimetics; biosynthesis; catechols; chemical kinetics; chemical structure; chemical structure function; dopamine; drug design /synthesis /production; gas chromatography mass spectrometry; high performance liquid chromatography; nuclear magnetic resonance spectroscopy; sulfur; antineoplastics; biological products; biomimetics; biosynthesis; catechols; chemical kinetics; chemical structure; chemical structure function; dopamine; drug design /synthesis /production; gas chromatography mass spectrometry; high performance liquid chromatography; nuclear magnetic resonance spectroscopy; sulfur

Ascidians (tunicates) contain compounds with a large range of pharmacological activities. With the most common of chemical ingredients, elemental sulfur and dopamine, an ascidian has developed a means to protect itself from predators using in essence chemical warfare. With lessons that marine organisms can provide, how might chemists seek the advent of new therapeutic substances from abundant and simple natural reagents? The problem is that we lack an understanding of the biosynthetic pathways that marine organisms use to make protective or otherwise purposeful molecules from benign common precursors. A long-term objective of this program is to synthesize sulfur?dopamine compounds that may have enhanced biological activity compared to what nature provides. This proposal outlines an experimental and theoretical organic chemistry approach to addressing the structure and synthesis of polysulfane antitumor compounds. Mechanistic information will be sought in reactions that mimic a biosynthetic process to help in designing new drugs. The goals of the research project are: (1) to examine the chemical mechanism for the formation of natural product antitumor polysulfanes formed from dopamine, and determine the product yields and product reaction profiles, (2) to identify the chemical form of sulfur that can add to dopamine and related natural aromatics such as catechol, (3) to define certain steps in the mechanism of formation of the polysulfur linkage, (4) to determine whether observed trends in heterocycle odd-even membered ring effects serve as a guide in the synthesis of pharmaceutically active polysulfane molecules, (5) to synthesize sulfur?dopamine compounds that have enhanced biological activity compared to what nature provides, and (6) to establish a collaborative research program such that the molecules produced in our laboratory will be examined as possible lead compounds, which may eventually be used clinically as antitumor and antibiotic agents. Research design and methods will involve experiments that utilize HPLC, GC/MS, NMR, and kinetic analyses for characterizations of the mechanisms. Theoretical calculations will be performed to discover the factors that are likely to influence polysulfane synthesis and decomposition with the aim of evaluating the viability of the intermediates.

海沿岸（双弯头）含有具有大量药理活性的化合物。最多 化学成分，元素硫和多巴胺的常见，海鞘已经开发了一种手段 保护自身免受本质化学战的捕食者的侵害。借助海洋生物可以 提供，化学家如何寻求新的治疗物质从丰富而简单的 天然试剂？问题是我们对海洋的生物合成途径缺乏了解 生物体用来从良性共同前体中产生保护性或有目的的分子。一个 该程序的长期目标是合成可能增强的硫的多巴胺化合物 与自然所提供的生物活性相比。该建议概述了实验和理论 有机化学方法来解决多硫烷抗肿瘤化合物的结构和合成。 将在模仿生物合成过程的反应中寻求机械信息，以帮助设计 新药。研究项目的目标是：（1）检查形成的化学机制 由多巴胺形成的天然产物抗肿瘤多硫硫硫硫代，并确定产物的产量和 产品反应曲线，（2）确定可以添加到多巴胺和相关的硫的化学形式 自然芳香剂，例如儿茶酚，（3），以定义形成机理的某些步骤 多硫连接，（4）确定观察到的杂环奇数构成环效应的趋势是否存在 作为合成药物活性多硫烷分子的指南，（5）合成 与自然所提供的相比，具有增强生物学活性的硫？多巴胺化合物， （6）建立一个协作研究计划，以使我们实验室产生的分子将是 被检查为可能的铅化合物，最终可以在临床上用作抗肿瘤和抗生素 代理商。研究设计和方法将涉及使用HPLC，GC/MS，NMR和动力学的实验 分析机制的特征。将执行理论计算以发现 可能影响多硫代合成和分解的因素，目的是评估 中间体的生存能力。