Functional analogues of bleomycin: DNA cleavage by bleomycin and hemin-intercalators

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Abstract
New hemin-intercalators (Hem-G''s) that cleve DNA were synthesized, on the basis of 2-amino-6-methyldipyrido[1,2-a:3'',2''-d]imidazole (Glu-P-1) as an intercalator moiety. Hem-G''s, which possess an intramolecular ligand of the ferrous ion (a histidine or imidazole moiety), cleave DNA very efficiently and act at guanine-pyrimidine sequences preferentially. Bleomycin (BLM) also cleaved DNA with the same base-sequence selectivity shown by Hem-G''s. The 5''-terminus of the DNA fragments cleaved by Hem-G''s or by BLM is a phosphoryl group, while the 3''-terminus of the cleaved DNA fragments does not possess a 3''-phosphoryl group. There are more than three kinds of 5''-end 32P-labeled DNA fragments, which can be substrates of terminal deoxynucleotidyl transferase (TdT). One of the 3''-termini of the cleaved DNA fragments is a 3''-hydroxy group. The mobility of the 3''-end 32P-labeled DNA fragment cleaved by Hem-G''s or by BLM corresponds to the removal of pyrimidine bases having guanine at the 5''-side. The mobility of one kind of the cleaved 5''-end 32P-labeled DNA fragments corresponds to the removal of guanine having pyrimidine at the 3''-side, followed by 3''-dephosphorylation. We propose that there exist plural mechanisms for DNA cleavage by Hem-G''s or by BLM. The deduced structures of the cleaved DNA fragments suggest that one of the mechanisms involves deletion of two nucleotide units from DNA.