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The antitumor antibiotic (+)-CC-1065 caM alkylate N3 of guanine in certain sequences. A previous high-field ’H NMR stuffy on the (+)-CC-1065d[GCGCAAITG*CGC]₂, adduct (* indicates the drug alkylation site) showed that drug modification on N3 of guanine results in protonation of the cross-strand cytosine (Park, H.-J.; Hurley, L. H. J.,Am. Chem. Soc. 1997, ff9,629.). In this contribution we describe a further analysis of the NMR data sets together with restrained molecular dynamics. This study provides not only a solution structure of the (+)-CC-1065(N3-guanine) DNA duplex adduct but also new insight into the molecu1ar basis for the sequence specifc interaction between (+)-CC-1065 and N3-guanine in the DNA duplex. On the basis of NOESY data, we propose that the narrow minor groove at the 7T8T step and conformational kinks at the junctions of 16C17A and 18A19T are both related to DNA bonding in the drug DNA adduct. Analysis of the one-dimensional ¹H NMR (inH₂0) data and Rmd trajectories strongly suggests that hydrogen bonding linkages between the 8-OH group of the (+)-CC-1065 A-sub- unit and the 9GlOC phosphate via a water molecule are present. All the phenomena observed here in the(+)-CC-1065(N3-guanine) adduct at 5’-AATTG’are reminiscent of those obtained from the studies on the (+)-CC-1065(N3-adenine) adduct at 5’-AGTTA’, suggesting that (+)-CC-1065 takes advantage of the conformational flexibility of the 5’-Tpu step to entrap the bent structure required for the covalent bonding reaction. This study reveals a common molecular basis for (+)-CC-1065 alkylation at both 5’-TTG" arid 5’-TTA’, which involves a trapping out of sequence-dependent DNA conformational flexibility as well as sequence-dependent general acid and general base catalysis by duplex DNA.
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