Solid-phase synthesis of bleomycin group antibiotics. Construction of a 108-member deglycobleomycin library

Christopher J. Leitheiser, Kenneth L. Smith, Michael J. Rishel, Shigeki Hashimoto, Kazuhide Konishi, Craig J. Thomas, Chunhong Li, Michael M. McCormick, Sidney M. Hecht

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

The bleomycins (BLMs) are structurally related glycopeptide antibiotics isolated from Streptomyces verticillus that mediate the sequence-selective oxidative damage of DNA and RNA. Deglycobleomycin, which lacks the carbohydrate moiety, cleaves DNA analogously to bleomycin itself, albeit less potently, and has been used successfully for analyzing the functional domains of bleomycin. Although structural modifications to bleomycin and deglycobleomycin have been reported, no bleomycin or deglycobleomycin analogue having enhanced DNA cleavage activity has yet been described. The successful synthesis of a deglycobleomycin on a solid support has permitted the facile solid-phase synthesis of 108 unique deglycobleomycin analogues through parallel solid-phase synthesis. Each of the deglycobleomycin analogues was synthesized efficiently; the purity of each crude product was greater than 60%, as determined by HPLC integration. The solid-phase synthesis of the deglycobleomycin library provided near-milligram to milligram quantities of each deglycobleomycin, thereby permitting characterization by 1H NMR and high-resolution mass spectrometry. Each analogue demonstrated supercoiled plasmid DNA relaxation above background cleavage; the library included two analogues that mediated plasmid relaxation to a greater extent than the parent deglycobleomycin molecule.

Original languageEnglish (US)
Pages (from-to)8218-8227
Number of pages10
JournalJournal of the American Chemical Society
Volume125
Issue number27
DOIs
StatePublished - Jul 9 2003
Externally publishedYes

ASJC Scopus subject areas

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

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    Leitheiser, C. J., Smith, K. L., Rishel, M. J., Hashimoto, S., Konishi, K., Thomas, C. J., Li, C., McCormick, M. M., & Hecht, S. M. (2003). Solid-phase synthesis of bleomycin group antibiotics. Construction of a 108-member deglycobleomycin library. Journal of the American Chemical Society, 125(27), 8218-8227. https://doi.org/10.1021/ja021388w