Zorbamycin has a different DNA sequence selectivity compared with bleomycin and analogues

Abstract

Bleomycin (BLM) is used clinically in combination with a number of other agents for the treatment of several types of tumours. Members of the BLM family of drugs include zorbamycin (ZBM), phleomycin D1, BLM A2 and BLM B2. By manipulating the BLM biosynthetic machinery, we have produced two new BLM analogues, BLM Z and 6′-deoxy-BLM Z, with the latter exhibiting significantly improved DNA cleavage activity. Here we determined the DNA sequence specificity of BLM Z, 6′-deoxy-BLM Z and ZBM, in comparison with BLM, with high precision using purified plasmid DNA and our recently developed technique. It was found that ZBM had a different DNA sequence specificity compared with BLM and the BLM analogues. While BLM and the BLM analogues showed a similar DNA sequence specificity, with TGTA sequences as the main site of cleavage, ZBM exhibited a distinct DNA sequence specificity, with both TGTA and TGTG as the predominant cleavage sites. These differences in DNA sequence specificity are discussed in relation to the structures of ZBM, BLM and the BLM analogues. Our findings support the strategy of manipulating the BLM biosynthetic machinery for the production of novel BLM analogues, difficult to prepare by total synthesis; some of which could have beneficial cancer chemotherapeutic properties.

The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA

“…The DNA sequence specificity of these three bleomycin analogues was also investigated and it was observed that bleomycin, BLM Z, and 6′-deoxy-BLM Z were very similar, but in comparison, ZBM had a different sequence specificity profile [ 174 ]. Bleomycin, BLM Z, and 6′-deoxy-BLM Z were found to mainly cleave at 5′-TGT*A sequences; while the cleavage preference of ZBM was 5′-TGT*G and 5′-TGT*A [ 174 ].…”