APPROACHES TO CHARACTERIZATION OF ANTIINFECTIVE AGENTS

这个项目的主要重点是分离和表征 用于治疗传染病的新化学类型。 这 包括涉及仪器开发的研究， 快速和彻底的分析复杂的生物活性有机化合物 生物混合物。 我们的目标是整合最强大的工具 可用于有机物的纯化和结构测定 一个单一的系统，同时能够回收近95 %的纯化样品用于生物学评价。 最 将研究有前途的代谢物的结构-活性 关系（SAR）使用半合成，微生物转化和 分子模拟 在过去的几十年里，天然产物的研究已经产生了 来自海洋环境的数千种新型有机化合物。的 指导这些分离的生物测定通常是抗微生物的， 抗肿瘤、抗病毒或抗肿瘤的。 几乎没有采取什么措施来 探索海洋，寻找具有抗艾滋病毒、艾滋病、结核病活性的化合物 和其他传染病。此外，由于限制 与传统的自给式水下呼吸有关 仪器（SCUBA），大多数化合物的特征在于从 海洋环境是浅水收集（-30米）的结果。 博士药物发现研究实验室的迈克尔·博伊德和 国家癌症研究所的研究表明， 筛选已被证明是发现 全新的化学型，甚至没有怀疑有相关的生化 特性. 这项研究计划的目的是 收集和筛选海洋样本，以寻找可能的艾滋病毒治疗方法， 来自海洋深处和位置的艾滋病OI 未开发的 这些提取物的活性成分显示出有希望的活性 将使用制备和半制备高压分离 液相色谱法（HPLC）与NMR和FTMS连接。 化学 生物活性次级代谢产物的结构将是 使用LC-NMR-FTMS和2D NMR测定。方法来提供 通过合成、半合成进行体内试验的足量 或将针对有前景的化合物进行再分离。SAR研究 将利用化学和微生物转化， 生物活性次级代谢物结合分子 建模研究。

The primary focus of this project is the isolation and characterization of new chemotypes for the treatment of infectious diseases. This includes research involving the development of instrumentation for the rapid and thorough analysis of bioactive organic compounds in complex biological mixtures. Our goal is to integrate the most powerful tools available for the purification and structure determination of organic materials into a single system while being able to recover nearly 95 percent of the purified sample for biological evaluation. The most promising metabolites will be studied for structure-activity relationships (SAR) using semi-synthesis, microbial transformations and molecular modeling. Natural product research during the last few decades has yielded thousands of novel organic compounds from the marine environment. The bioassays guiding these isolations typically have been antimicrobial, antitumor, antiviral or antiinflammatory. Little has been done to explore the oceans for compounds with activity against HIV, AIDS OI, TB and other infectious diseases. Additionally, because of the limits associated with the conventional self-contained underwater breathing apparatus (SCUBA), the majority of the compounds characterized from the marine environment are the results of shallow water collections (-30m). Dr. Michael Boyd, of the Laboratory of Drug Discovery Research and Development at the National Cancer Institute indicates that mass screening has proved to be the most effective means of discovering entirely new chemotypes not even suspected to have relevant biochemical properties. The objective of this proposed research program is to collect and screen marine samples for possible treatments of HIV and AIDS OI from depths and locations in the ocean which have remained unexplored. The active component(s) of those extracts showing promising activity will be isolated using preparative and semi-preparative high pressure liquid chromatography (HPLC) interfaced with NMR and FTMS. The chemical structures of the biologically active secondary metabolites will be determined with the use of LC-NMR-FTMS and 2D NMR. Methods for providing sufficient quantities for in vivo testing via synthesis, semi-synthesis or reisolation will be addressed for promising compounds. SAR studies will be conducted utilizing chemical and microbial transformations of biologically active secondary metabolites combined with molecular modeling studies.