S51: Deciphering the biosynthesis of pyrrolobenzodiazepines and bioengineering production of their analogues

Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. We have sequenced and functionally characterized the biosynthetic gene clusters of sibiromycin and tomaymycin. We will report on our progress to establish the biosynthetic pathway of these compounds and to produce glycosylated analogs of PBDs.