Structure-activity Relationships Involved in the Site-specific Fragmentation of Linear Duplex DNAs by Talisomycin and Bleomycin Analogs

The fragmentation of Hind III- and Pst I-digested PM2 DNA and of Hind III-digested pBR322 DNA by bleomycin A2 and B2 and talisomycins A, B, S2b, and S10b was investigated. As observed by electrophoresis on agarose gels, the ethidium bromide staining band patterns produced following incubation of the various restriction endonuclease-digested DNAs with the compounds were different for the bleomycin analogs and for the talisomycin analogs. Quantitation of the degree of fragmentation of various segments of linear PM2 DNA by either bleomycin A2 or talisomycin A indicated that certain segments of the PM2 genome serve as better substrates than other segments for double-strand fragmentation by either of the two antitumor antibiotics. These results show that in this system bleomycin and talisomycin analog treatment of linear PM2 or pBR322 DNA resulted in breakage of DNA, producing different-length DNA fragments, and demonstrate the importance of the two amino acids and the 4-amino-4,6-dideoxy-L-talose sugar, which are located near the bithiazole in talisomycin but absent in the bleomycin structure in conferring a different site-specificity for DNA fragmentation to talisomycin than to bleomycin.