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

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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.