STRUCTURES OF ANTIBIOTICS AND RELATED COMPOUNDS

抗生素及相关化合物的结构

基本信息

批准号：
6615110
负责人：
ROBERT M. COATES
金额：
$ 28.72万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1977
资助国家：
美国
起止时间：
1977-05-01 至 2005-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6615110
关键词：
Escherichia coli Porifera Saccharomyces cerevisiae Tunicata alternatives to animals in research antibiotics antineoplastic antibiotics chemical structure cyclic peptides drug discovery /isolation drug screening /evaluation pharmacokinetics photosynthetic bacteria saltwater environment

项目摘要

DESCRIPTION (verbatim from applicant's abstract): The present research proposal is designed to test the hypothesis that marine organism-derived natural products can provide clinically useful pharmaceutical agents. Specifically, antitumor agents will be sought, and to a lesser degree antimicrobial, antiviral, and immunosuppressive agents. These represent multiple goals of which the antitumor target is the most readily accessible and is now in sight. Research will focus on ecteinascidin 743 (ET 743) and dehydrodidemnin B (Aplidine). These two compounds from our laboratory are now in clinical trial in Europe and North America as anticancer agents. ET 743, from the tunicate (sea squirt) Ecteinascidia turbinata, currently in Phase II clinical trials, is present in only 1 g/ton of the tunicate and efforts will be made to increase the quantity available for human testing by defining the biosynthetic pathway, including precursors and intermediates. Attempts will be made to establish whether a symbiotic microorganism may actually produce ET 743. More active derivatives and analogs of ET743 will be sought and developed. Oxidative degradation will be studied to characterize the metabolites and perhaps to slow drug degradation in patients. Aplidine (dehydrodidemnin B) is currently in Phase I trials and may be regarded as a second-generation analog of didemnin B (DB). The latter reached Phase II trials and showed promise in treating non-Hodgkins lymphoma but was dropped due to cardiac toxicity. By contrast Aplidine is up to 30 times as active as DB and lacks its cardiotoxicity. Biosynthesis of Aplidine and DB will be studied in Spain and the Caribbean, respectively, but is complicated by its symbiotic relationship with the cyanobacterium Synechocystis trididemniii, which will be studied separately. Ring opened analogs of Aplidine and DB will be prepared to see whether they represent biosynthetic intermediates or degradation products of the cyclic depsipeptide. Amide analogs of the Hip and Thr units will also be prepared, to stabilize the cyclic depsipeptides and hinder in vivo hydrolysis. A cyanobacterial product, a mixture of oscillacidins A and B from an Oscillatoria species, appears to be toxic to L1210 leukemia cells and is being investigated for its unique structure, different from the hepatotoxins microcystins and nodularin, which are cyclic heptapeptides and pentapeptides containing the novel acid Adda.

描述（逐字研究来自申请人的摘要）：本研究建议旨在检验海洋生物衍生自然的假设产品可以提供临床上有用的药物。具体来说，将寻求抗肿瘤剂，并在较小程度上抗菌剂抗病毒和免疫抑制剂。这些代表了多个目标抗肿瘤目标是最容易访问的目标，现在可以看到。研究将重点介绍雌激素743（ET 743）和脱氢烯B （aplidine）。我们实验室的这两种化合物现在正在临床试验中在欧洲和北美，是抗癌代理商。 ET 743，来自皮象（Sea Squirt）Ecteinascidia turbinata，目前在 II期临床试验仅以1克/吨的福音仪和将努力增加可用于人类测试的数量定义生物合成途径，包括前体和中间体。将尝试确定共生微生物是否可以实际产生ET 743。ET743的更多活性衍生物和类似物将是寻求和发展。将研究氧化降解以表征代谢物，可能会减慢患者的药物降解。 aplidine（脱氢二烯B）目前正在I期试验中，可能会被认为作为Dodemnin B（db）的第二代类似物。后者达到了II期试验并显示出治疗非霍奇金斯淋巴瘤的希望，但被丢弃心脏毒性。相比之下，同二氨酸的活性高达30倍，并且缺乏其心脏毒性。邻肽和DB的生物合成将在西班牙和加勒比海地区，但由于其共生而变得复杂与蓝细菌合成藻的关系，这将是单独研究。环拟氨酸和DB的环类似物将做好准备查看它们是代表生物合成中间体还是降解产物循环深度肽。臀部和THR单元的酰胺类似物也将是制备，以稳定循环二肽并阻碍体内水解。蓝细菌产物，载酸A和B的混合物振荡物种，似乎对L1210白血病细胞有毒，并且正在研究其独特的结构，与肝毒素不同微囊蛋白蛋白和结节蛋白，它们是环状七肽和五肽包含新颖的酸添加剂。