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: 8228017
• 负责人: STEVEN E ROKITA
• 金额: $ 6.25万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228017
• 关键词: Actinobacteria class; 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; public health relevance; pyrrolobenzodiazepine; research study; sibanomicin; sibiromycin; sibirosamine; sugar; tomaymycin; vector

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：次级代谢产物通常由生物体产生，作为防御机制的一部分或促进繁殖。次级代谢产物的化学多样性反映了生物合成途径中存在的各种酶促反应。因此，这些途径是令人兴奋的新转化和前所未有的酶的恒定和丰富的来源。此外，通过阐明生物合成途径获得的遗传和酶知识可用于生产化学变化的次级代谢产物。吡咯并[1，4]苯并二氮杂卓类抗生素是一类存在于放线菌中的具有序列选择性的DNA烷基化试剂。SJG-136用于治疗转移性或不可切除的实体瘤的I期人体临床试验于2004年开始。微生物学、分子生物学和酶学技术将用于本提案，以阐明吡咯并[1，4]苯并二平生产的生物化学基础。具体而言，我们建议1）鉴定托马霉素和西比罗霉素的生物合成基因簇，2）产生新型糖基化PBD和PBD二聚体，3）表征生物合成途径中存在的独特酶促转化。公共 健康相关性吡咯并苯二氮卓类（PBD）是由细菌天然产生的具有强效抗肿瘤特性的化合物。PBD对多种癌症的显著广谱活性和有效性鼓励了新PBD的开发。例如，SJG-136目前正在进行针对转移性和不可切除的实体瘤的I期临床试验。我们打算研究自然界是如何合成这些化合物的。这样获得的遗传学和酶学知识然后可以用于生产这些化合物的新类似物。本提案中讨论了此类应用的实例。