APPROACHES TO CHARACTERIZATION OF ANTIINFECTIVE AGENTS

该项目的主要重点是用于治疗传染病的新化学型的分离和表征。 这包括涉及开发用于快速和彻底分析复杂生物混合物中生物活性有机化合物的仪器的研究。 我们的目标是将有机材料纯化和结构测定的最强大工具集成到一个系统中，同时能够回收近95%的纯化样品用于生物评价。 将使用半合成、微生物转化和分子建模来研究最有希望的代谢物的结构-活性关系（SAR）。在过去的几十年里，天然产物的研究已经从海洋环境中产生了数千种新的有机化合物。指导这些分离的生物测定通常是抗微生物、抗肿瘤、抗病毒或抗肿瘤的。 在海洋中探索具有抗艾滋病毒、艾滋病、结核病和其他传染病活性的化合物的工作很少。此外，由于与传统的自给式水下呼吸器（SCUBA）相关的限制，从海洋环境中表征的大多数化合物是浅水收集（~ 30米）的结果。美国国家癌症研究所药物发现研究与开发实验室的Michael Boyd博士指出，大规模筛查已被证明是发现全新化学型的最有效手段，甚至怀疑它们具有相关的生化特性。 这项拟议研究计划的目的是收集和筛选海洋样本，用于从海洋深处和尚未探索的位置治疗艾滋病毒和艾滋病OI。将使用制备型和半制备型高压液相色谱法（HPLC）结合NMR和FTMS分离显示有希望活性的提取物的活性组分。 将使用LC-NMR-FTMS和2D NMR测定生物活性次级代谢产物的化学结构。对于有前景的化合物，将讨论通过合成、半合成或再分离提供足够量用于体内测试的方法。将利用生物活性次级代谢产物的化学和微生物转化结合分子建模研究进行SAR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.