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：
8037037
负责人：
STEVEN E ROKITA
金额：
$ 23.46万
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：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037037
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

项目摘要

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）：次生代谢物通常由生物体作为防御机制的一部分或促进生殖产生。次生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型转变和前所未有的酶的恒定而丰富的来源。此外，可以利用阐明生物合成途径获得的遗传和酶促知识来生产化学变化的二级代谢产物。吡罗洛[1,4]苯二氮卓类是在放线菌中发现的一类有效抗肿瘤抗生素，是序列选择性DNA烷基化剂。 SJG-136对转移性或不可切除的实体瘤治疗的1阶段临床试验开始于2004年。在该提案中，将使用微生物学，分子生物学和酶学技术来阐明吡咯并阐明吡咯的生物化学[1,4] Benzodiapines的生产。具体而言，我们建议1）确定tomaymycin和sibiromycin的生物合成基因簇，2）产生新型的糖基化PBD和PBD二聚体，以及3）表征生物合成途径中存在的独特酶促转化。民众健康相关性吡咯苯二氮卓类（PBD）是具有有效抗肿瘤特性的细菌自然产生的化合物。 PBD的广泛活动和针对各种癌症的有效性鼓励了新的PBD的发展。例如，SJG-136目前正在针对转移性和不可切除的实体瘤的I期临床试验中。我们建议研究自然如何进行这些化合物的合成。因此，因此获得的遗传学和酶学知识可用于生产这些化合物的新类似物。此提案中讨论了此类应用的示例。