Biosynthesis of Pyrrolo[1,4]benzodiazepines, potent antitumor antibiotics

吡咯并[1,4]苯二氮卓类药物的生物合成，强效抗肿瘤抗生素

• 批准号: 7930272
• 负责人: STEVEN E ROKITA
• 金额: $ 17.39万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7930272
• 关键词: Actinobacteria class; Actinomyces; Alkylating Agents; Anabolism; Anthramycin; Antineoplastic Agents; Bacteria; Base Sequence; Benzodiazepines; Biochemical Reaction; Biochemistry; Biological; Biological Factors; Chemicals; Chemistry; Clinical Trials; DNA; Defense Mechanisms; Development; Disease; Effectiveness; Engineering; Enzymes; Fermentation; Foundations; Gene Cluster; Genes; Genetic; Human; Knowledge; Label; Licensing; Malignant Neoplasms; Marketing; Medicine; Metabolic; Methodology; Microbiology; Molecular Biology; National Cancer Institute; Nature; Open Reading Frames; Organism; Pathway interactions; Pharmacologic Substance; Phase; Phase I Clinical Trials; Production; Property; Pyrroles; Reaction; Reporting; Reproduction; Research; SJG-136; Solid Neoplasm; Source; Specificity; Streptomyces; Techniques; Tyrosine; United Kingdom; United States; Unresectable; analog; anticancer research; antineoplastic antibiotics; chemical synthesis; dimer; interest; novel; overexpression; pyrrolobenzodiazepine; research study; sibanomicin; sibiromycin; sibirosamine; sugar; tomaymycin; vector

Secondary metabolites are usually produced by an organism as part of a defense mechanism or to facilitate reproduction. The chemical diversity of secondary metabolites mirrors the variety of enzymatic reactions present in the biosynthetic pathways. Therefore, these pathways are a constant and rich source of exciting novel transformations and unprecedented enzymes. In addition, the genetic and enzymatic knowledge acquired by elucidating the biosynthetic pathways can be exploited for the production of chemically varied secondary metabolites. Pyrrolo[1,4]benzodiazepines, a class of potent antitumor antibiotics found in actinomycetes, are sequence selective DNA alkylating agents. Phase 1 human clinical trials of SJG-136 for the treatment of metastatic or unresectable solid tumors were started in 2004. Microbiology, molecular biology and enzymological techniques will be used in this proposal to elucidate the biochemistry underlying pyrrolo[1,4]benzodiapines' production. Specifically, we propose to 1) identify the biosynthetic gene clusters for tomaymycin and sibiromycin, 2) produce novel glycosylated PBDs and PBD dimers, and 3) characterize the unique enzymatic transformations present in the biosynthetic pathway. Pyrrolobenzodiazepines (PBDs) are compounds naturally produced by bacteria with potent antitumor properties. PBDs' remarkable broad spectrum of activities and effectiveness against a wide variety of cancers encourages the development of new PBDs. For instance, SJG-136 is currently in phase I clinical trials against metastatic and unresectable solid tumors. We are proposing to study how nature carries out the synthesis of these compounds. The genetic and enzymological knowledge so obtained can then be used for production of new analogs of these compounds. Examples of such application are discussed in this proposal.

次生代谢物通常由生物体产生，作为 防御机制或促进繁殖。化学成分的多样性 次生代谢物反映了存在的酶反应的多样性 生物合成途径。因此，这些途径是一个持续和丰富的来源 令人兴奋的新奇变化和前所未有的酶。此外， 通过阐明生物合成获得的遗传和酶学知识 可以利用各种途径来生产不同化学成分的次生物质 代谢物。一类有效的抗肿瘤抗生素--吡咯并[1，4]苯二氮卓类药物 在放线菌中发现的是序列选择性DNA烷基化试剂。阶段1 SJG-136治疗转移性或不能切除肿瘤的人体临床试验 实体肿瘤始于2004年。微生物学、分子生物学和 在这项建议中将使用酶学技术来阐明 吡咯并[1，4]苯并二平生产的生物化学。具体来说，我们 建议1)鉴定托马霉素生物合成基因簇和 西比罗霉素，2)产生新的糖基化的PBD和PBD二聚体，以及3) 表征生物合成中存在的独特的酶转化 路径。吡咯洛苯并二氮卓类化合物(PBDS)是一种天然产生的化合物 具有强大的抗肿瘤特性的细菌。PBDS惊人的广泛性 抗击多种癌症的活动和成效鼓励 开发新的多氯联苯。例如，SJG-136目前处于I期临床 治疗转移性和不可切除实体肿瘤的试验。我们正在提议 研究自然界是如何合成这些化合物的。基因和 这样获得的酶学知识可以用于生产新的 这些化合物的类似物。在本文中讨论了这种应用的例子 求婚。