Two structurally novel bleomycin (BLM) analogs were prepared by total synthesis to permit the evaluation of the role of individual thiazole moieties in the processes of bleomycin-mediated oxygen activation and DNA degradation. Each of the compounds was structurally related to deglycobleomycin demethyl A2 but contained an S-methyl-l-cysteine moiety in lieu of one of the two thiazoles normally present in bleomycin. In common with bleomycin and deglycobleomycin, both monothiazole BLMs were found to be excellent catalysts for the oxygenation of low molecular weight substrates such as naphthalene and styrene and also mediated the demethylation of N,N-dimethylaniline. However, both of the monothiazole BLMs were much less effective than bleomycin or deglycobleomycin in promoting DNA degradation. Analysis of the effects of the monothiazole BLMs on 5′-and 3′-32P end labeled DNA duplexes indicated that cleavage occurred without discernible sequence selectivity. These results demonstrate that the bithiazole moiety in BLM is not required for O2 activation or for the oxygenation and oxidation of low molecular substrates in what are presumably biomolecular processes. However, the bithiazole clearly does contribute to the efficiency of bleomycin-mediated DNA degradation and to the sequence selectivity of DNA strand scission by bleomycin.
ASJC Scopus subject areas
- Colloid and Surface Chemistry