Sequence specificity of DNA alkylation by the antitumor natural product leinamycin

Reaction with thiol converts the antitumor natural product leinamycin to an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. The sequence specificity for DNA alkylation by this structurally novel compound has not previously been examined. It is reported here that leinamycin shows significant (>10-fold) preferences for alkylation at the 5‘-G in 5‘-GG and 5‘-GT sequences. The sequence preferences for activated leinamycin are significantly different from that observed for the structurally simple episulfonium ion generated from 2-chloroethyl ethyl sulfide. DNA alkylation by activated leinamycin is inhibited by addition of salt (100 mM NaClO4), although the degree of inhibition is somewhat less than that seen for 2-chloroethyl ethyl sulfide. This result suggests that electrostatic interactions between the activated leinamycin and the N7-position of guanine residues facilitate efficient DNA alkylation. However, the observed sequence preferences for DNA alkylation by ac...