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

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.

海鞘（被囊动物）含有具有大范围药理活性的化合物。最 常见的化学成分，元素硫和多巴胺，海鞘已经发展出一种方法， 保护自己免受掠食者的攻击本质上是化学战。海洋生物可以 化学家如何从丰富而简单的物质中寻找新的治疗物质， 天然试剂？问题是，我们缺乏对海洋生物合成途径的了解， 生物体用来从良性的普通前体中制造保护性或其他目的性分子。一 这项计划的长期目标是合成硫磺？多巴胺化合物可能增强了 生物活性与自然提供的相比。该提案概述了一个实验和理论 有机化学方法来解决多硫烷抗肿瘤化合物的结构和合成。 将在模拟生物合成过程的反应中寻找机制信息，以帮助设计 新药本课题的研究目标是：（1）研究其形成的化学机理 的天然产物抗肿瘤聚硫烷形成的多巴胺，并确定产品的产率和 产品反应概况，（2）确定硫的化学形式，可以添加到多巴胺和相关 天然芳香族化合物，如邻苯二酚，（3）定义形成的机制中的某些步骤， 多硫键，（4）以确定是否观察到杂环奇偶元环效应的趋势 作为药物活性聚硫烷分子合成的指导，（5）合成 硫磺？与自然界提供的物质相比，多巴胺化合物具有增强的生物活性， (6)建立一个合作研究项目，这样我们实验室生产的分子将被 作为可能的先导化合物进行了研究，最终可能在临床上用作抗肿瘤和抗生素 剂.研究设计和方法将涉及利用HPLC，GC/MS，NMR和动力学的实验。 分析了机制的特征。将进行理论计算以发现 可能影响聚硫烷合成和分解的因素，目的是评估 中间体的生存能力。