Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: Three new products generated in the mithramycin producer streptomyces argillaceus through combinatorial biosynthesis

Lily L. Remsing, Ana M. González, Mohammad Nur-e-Alam, M. José Fernández-Lozano, Alfredo F. Braña, Uwe Rix, Marcos A. Oliveira, Carmen Méndez, José A. Salas, Jürgen Rohr

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW. In this last step of the MTM biosynthesis, a keto group of the pentyl side chain is reduced to a secondary alcohol, and we anticipated the generation of an MTM derivative with an additional keto group in the 3-side chain. Insertional inactivation of mtmW, a gene located ca. 8 kb downstream of the mithramycin-PKS genes, yielded an S. argillaceus mutant, which accumulated three new mithramycin analogues, namely mithramycin SA, demycarosyl-mithramycin SK, and mithramycin SK (MTM-SK). The structures of these three compounds confirmed indirectly the proposed role of MtmW in MTM biosynthesis. However, the new mithramycin derivatives bear unexpectedly shorter 3-side chains (ethyl or butyl) than MTM, presumably caused by nonenzymatic rearrangement or cleavage reactions of the initially formed pentyl side chain with a reactive β-dicarbonyl functional group. The major product, MTM-SK, was tested in vitro against a variety of human cancer cell lines, as well as in an in vitro toxicity assay, and showed an improved therapeutic index, in comparison to the parent drug, MTM.

Original languageEnglish
Pages (from-to)5745-5753
Number of pages9
JournalJournal of the American Chemical Society
Volume125
Issue number19
DOIs
StatePublished - May 14 2003

ASJC Scopus subject areas

  • Catalysis
  • Chemistry (all)
  • Biochemistry
  • Colloid and Surface Chemistry

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