Total synthesis of deamido bleomycin A2, the major catabolite of the antitumor agent bleomycin

Ying Zou, Nour Eddine Fahmi, Corine Vialas, Guy M. Miller, Sidney Hecht

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Metabolic inactivation of the antitumor antibiotic bleomycin is believed to be mediated exclusively via the action of bleomycin hydrolase, a cysteine proteinase that is widely distributed in nature. While the spectrum of antitumor activity exhibited by the bleomycins is believed to reflect the anatomical distribution of bleomycin hydrolase within the host, little has been done to characterize the product of the putative inactivation at a chemical or biochemical level. The present report describes the synthesis of deamido-bleomycin demethyl A2 (3) and deamido bleomycin A2 (4), as well as the respective aglycones. These compounds were all accessible via the key intermediate Nα-Boc-Nβ-[1-amino-3(S)-(4-amino-3(S) (4-6-carboxy-5-methylpyrimidin-2-yl)propion-3-yl]-(S)-β-aminoalanine tert-butyl ester (16). Synthetic deamido bleomycin A2 was shown to be identical to the product formed by treatment of bleomycin A2 with human bleomycin hydrolase, as judged by reversed-phase HPLC analysis and IH NMR spectroscopy. Deamido bleomycin A2 was found to retain significant DNA cleavage activity in DNA plasmid relaxation assays and had the same sequence selectivity of DNA cleavage as bleomycin A2. The most significant alteration of function noted in this study was a reduction in the ability of deamido bleomycin A2 to mediate double-strand DNA cleavage, relative to that produced by BLM A2.

Original languageEnglish (US)
Pages (from-to)9476-9488
Number of pages13
JournalJournal of the American Chemical Society
Volume124
Issue number32
DOIs
StatePublished - Aug 14 2002
Externally publishedYes

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Bleomycin
Hydrolases
Antineoplastic Agents
DNA
DNA Cleavage
Antibiotics
Nuclear magnetic resonance spectroscopy
Assays
Esters
Diethylpropion
Cysteine Proteases
varespladib methyl
Plasmids
Magnetic Resonance Spectroscopy
High Pressure Liquid Chromatography
Anti-Bacterial Agents

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Total synthesis of deamido bleomycin A2, the major catabolite of the antitumor agent bleomycin. / Zou, Ying; Fahmi, Nour Eddine; Vialas, Corine; Miller, Guy M.; Hecht, Sidney.

In: Journal of the American Chemical Society, Vol. 124, No. 32, 14.08.2002, p. 9476-9488.

Research output: Contribution to journalArticle

Zou, Ying ; Fahmi, Nour Eddine ; Vialas, Corine ; Miller, Guy M. ; Hecht, Sidney. / Total synthesis of deamido bleomycin A2, the major catabolite of the antitumor agent bleomycin. In: Journal of the American Chemical Society. 2002 ; Vol. 124, No. 32. pp. 9476-9488.
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