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Mutasynthesis of a potent anticancer sibiromycin analogue.

ABSTRACT: Pursuit of the actinomycete pyrrolobenzodiazepine natural product sibiromycin as a chemotherapeutic agent has been limited by its cardiotoxicity. Among pyrrolobenzodiazepines, cardiotoxicity is associated with hydroxylation at position 9. Deletion of the methyltransferase gene sibL abolishes the production of sibiromycin. Supplementation of growth media with 4-methylanthranilic acid can substitute for its native 3-hydroxy congener. Cultures grown in this fashion yielded 9-deoxysibiromycin. In this study, we characterize the structure and biological activity of sibiromycin and 9-deoxysibiromycin methyl carbinolamines. Preliminary in vitro evidence suggests that 9-deoxysibiromycin exhibits reduced cardiotoxicity while gaining antitumor activity. These results strongly support further exploration of the production and evaluation of monomeric and dimeric glycosylated pyrrolobenzodiazepine analogues of sibiromycin.

SUBMITTER: Yonemoto IT

PROVIDER: S-EPMC3376188 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Mutasynthesis of a potent anticancer sibiromycin analogue.

Yonemoto Isaac T IT Li Wei W Khullar Ankush A Reixach Natàlia N Gerratana Barbara B

ACS chemical biology 20120323 6

Pursuit of the actinomycete pyrrolobenzodiazepine natural product sibiromycin as a chemotherapeutic agent has been limited by its cardiotoxicity. Among pyrrolobenzodiazepines, cardiotoxicity is associated with hydroxylation at position 9. Deletion of the methyltransferase gene sibL abolishes the production of sibiromycin. Supplementation of growth media with 4-methylanthranilic acid can substitute for its native 3-hydroxy congener. Cultures grown in this fashion yielded 9-deoxysibiromycin. In th ...[more]

PMID: 22390171

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