Nucleotide-specific cleavage and minor-groove interaction of DNA with esperamicin antitumor antibiotics.

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Abstract
The cleavage of DNA by esperamicin is greatly accelerated in the presence of thiol compounds. Oxygen and active oxygen-radical scavengers have no significant influence upon DNA strand breakage by esperamicin. The preferential cutting sites of esperamicin are at thymidylate residues, and the frequency of bases attacked (T > C > A > G) is different from that of calicheamicin (C >> T > A = G), neocarzinostatin (T > A > C > G), or bleomycin (C > T > A > G). Esperamicin preferentially attacks at T and C bases in oligopyrimidine sequences such as 5''-CTC-3'',5''-TTC-3'', and 5''-TTT-3''. In contrast to the preferred sites of cleavage by bleomycin, 5''-GT-3'' and 5''-GC-3'', the preferred sites of esperamicin-mediated DNA degradation are 5''-TG-3'' and 5''-CG-3'' sequences. The nucleotide-specific cleavage mode of esperamicin is significantly affected by pretreatment of DNA with netropsin and distamycin A, suggesting that interaction of esperamicin occurs through the minor groove of B-DNA. This is further supported by the asymmetric cleavage pattern to the 3'' side on the opposite strand of the DNA. The roles of the fucose-anthranilate moiety and the trisaccharide side chain of esperamicin in DNA binding and base recognition are discussed.