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（申请人摘要中的逐字记录）：目前的研究计划旨在检验海洋生物衍生的天然物质这一假设产品可以提供临床上有用的药剂。具体来说，将寻求抗肿瘤药物，并在较小程度上寻求抗菌药物，抗病毒剂和免疫抑制剂。这些代表了多个目标其中抗肿瘤靶点是最容易接近的并且现在就在眼前。研究将集中在 ecteinascidin 743 (ET 743) 和 deHydrodidemnin B （阿普立定）。我们实验室的这两种化合物目前正在进行临床试验在欧洲和北美作为抗癌剂。 ET 743，来自被囊类（海鞘）Ecteinascidia turbinata，目前位于 II 期临床试验，仅存在于被囊类动物中 1 克/吨将努力增加可用于人体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上生产 ET 743。更多活性衍生物和 ET743 类似物将寻求和发展。将研究氧化降解来表征代谢物，或许还可以减缓患者体内的药物降解。 Aplidine（deHydrodidemnin B）目前正处于 I 期试验中，可能会被视为作为 didemnin B (DB) 的第二代类似物。后者进入第二阶段试验并显示出治疗非霍奇金淋巴瘤的希望，但因失败而被放弃致心脏毒性。相比之下，Aplidine 的活性高达 DB 的 30 倍，缺乏其心脏毒性。 Aplidine 和 DB 的生物合成将在分别是西班牙和加勒比地区，但因其共生而变得复杂与蓝藻集胞藻 (Synechocystis triddemniii) 的关系，分别学习。 Aplidine 和 DB 的开环类似物将被制备看看它们是否代表生物合成中间体或降解产物环缩酚肽。 Hip 和 Thr 单元的酰胺类似物也将是制备，以稳定环状缩肽并阻碍体内水解。一种蓝藻产品，是来自藻类的振荡素 A 和 B 的混合物颤藻属物种，似乎对 L1210 白血病细胞有毒，目前正在研究中因其独特的结构而被研究，不同于肝毒素微囊藻毒素和节球菌素，它们是环状七肽和五肽含有新型酸Adda。