Mechanism of Formation of Polysulfane Anticancer Agents

聚硫烷抗癌剂的形成机理

• 批准号: 7778906
• 负责人: ALEXANDER GREER
• 金额: $ 17.51万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7778906
• 关键词: Address; Antibiotics; Antineoplastic Agents; Antitumor Natural Products; Benign; Biological; Catechols; Chemical Warfare; Chemicals; Dopamine; Goals; High Pressure Liquid Chromatography; Ingredients and Chemicals; Kinetics; Laboratories; Lead; Methods; Nature; Organic Chemistry; Pathway interactions; Pharmaceutical Preparations; Process; Reaction; Reagent; Research; Research Design; Research Project Grants; Research Support; Structure; Sulfur; Urochordata; antineoplastic antibiotics; ascidian; college; design; marine organism; novel therapeutics; programs; research study; trend

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.

海鞘类（被囊类）含有具有广泛药理活性的化合物。用最多的