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

基本信息

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
项目类别：
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

项目摘要

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，作为生物体的一部分防御机制或促进繁殖。化学多样性次级代谢物反映了存在于体内的各种酶促反应生物合成途径。因此，这些途径是一个持续而丰富的来源令人兴奋的新颖转变和前所未有的酶。此外，通过阐明生物合成获得的遗传和酶学知识可以利用途径来生产化学上不同的次级物质代谢物。吡咯并[1,4]苯二氮卓类药物，一类强效抗肿瘤抗生素存在于放线菌中，是序列选择性 DNA 烷化剂。第一阶段 SJG-136治疗转移性或不可切除性癌症的人体临床试验实体瘤研究始于2004年。微生物学、分子生物学和本提案将使用酶学技术来阐明吡咯并[1,4]苯二氮平生产的生物化学基础。具体来说，我们建议 1) 鉴定茅霉素的生物合成基因簇和西伯霉素，2) 产生新型糖基化 PBD 和 PBD 二聚体，以及 3) 表征生物合成中存在的独特酶促转化途径。吡咯并苯二氮卓类 (PBD) 是天然产生的化合物具有有效抗肿瘤特性的细菌。 PBD 具有显着的广谱性针对多种癌症的活动和有效性鼓励开发新的PBD。例如，SJG-136目前正处于I期临床针对转移性和不可切除实体瘤的试验。我们提议研究大自然如何合成这些化合物。遗传和如此获得的酶学知识可以用于生产新的这些化合物的类似物。本文讨论了此类应用的示例提议。