Mechanism of Formation of Polysulfane Anticancer Agents

海鞘(囊状物)含有具有广泛药理活性的化合物。拥有最多的 海鞘是一种常见的化学成分，元素硫和多巴胺，它已经开发出一种方法来 在本质上使用化学战来保护自己免受捕食者的伤害。海洋生物可以学到的经验 提供，化学家如何从丰富和简单的中寻求新的治疗物质的出现 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的或有目的的分子。一个 该计划的长期目标是合成硫多巴胺化合物，这些化合物可能会增强 生物活动与自然提供的相比。该提案概述了一种实验和理论上的 有机化学方法解决聚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械信息，以帮助设计 新药。该研究项目的目标是：(1)研究形成的化学机制 由多巴胺形成的天然产物抗肿瘤多磺酸的含量，并测定产物产率和 产品反应概况，(2)确定硫磺的化学形态，可添加到多巴胺和相关的 天然芳香族，如邻苯二酚，(3)定义形成机理中的某些步骤 多硫键，(4)确定观察到的杂环奇偶环效应的趋势 用于指导合成具有药用活性的聚硫烷分子，(5)合成 硫磺？与自然提供的相比，具有增强生物活性的多巴胺化合物，以及 (6)建立合作研究计划，使我们实验室生产的分子 被检测为可能的先导化合物，最终可能作为抗肿瘤和抗生素用于临床 探员们。研究设计和方法将包括利用高效液相色谱、GC/MS、核磁共振和动力学的实验 对机构的表征进行分析。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，目的是评价 中间体的生存能力。

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.