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.

次级代谢物通常由生物体产生，作为代谢产物的一部分。 防御机制或促进繁殖。化学多样性 次级代谢产物反映了存在于细胞中的各种酶促反应， 生物合成途径因此，这些途径是一个恒定的和丰富的来源 令人兴奋的新颖转变和前所未有的酶。此外该 遗传和酶知识获得阐明生物合成 可以利用这些途径来生产化学上不同的次生代谢产物， 代谢物。吡咯并[1，4]苯并二氮杂类抗生素 在放线菌中发现，是序列选择性DNA烷基化剂。1期 SJG-136用于治疗转移性或不可切除的 实体瘤始于2004年。微生物学、分子生物学和 酶学技术将用于本提案中，以阐明 吡咯并[1，4]苯并二吖庚因产生的生物化学基础。我们特别 建议1）鉴定tomaymycin的生物合成基因簇， 西比罗霉素，2）产生新糖基化PBD和PBD二聚体，和3） 表征生物合成中存在的独特酶促转化 通路吡咯并苯并二氮杂卓（PBD）是由以下化合物天然产生的化合物： 具有强效抗肿瘤特性的细菌。PBD的显著广谱 针对各种癌症的活动和有效性鼓励 开发新的PBD。例如，SJG-136目前处于I期临床阶段， 针对转移性和不可切除的实体瘤的试验。我们建议 研究大自然如何合成这些化合物。的遗传和 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。这种应用的例子在此讨论 提议