Highly selective DNA alkylation at the 5′ side G of a 5′GG3′ sequence by an aglycon model of pluramycin antibiotics through preferential intercalation into the GG step

Altromycin B and kapurimycin Ag are new members of the pluramycin family antibiotics that alkylate N7 of guanine (G) in duplex DNA at an epoxide subunit attached to the C2 position of the pyranone ring. While 5'AG3' selective alkylation by altromycin B was accounted for by selective binding to the sequence, it remained uncertain why kapurimycin A(3), which is structurally similar to an aglycon part of altromycin B but has an epoxide subunit with an opposite absolute configuration, selectively alkylates 5' G of the 5'GG3' sequence. To clarify the molecular basis for the sequence-selective G alkylation by kapurimycin A(3), we have examined the DNA cleavage sequence selectivity of an enantiomeric pair of an aglycon model of pluramycin antibiotics and calculated total energy change upon intercalation of the model into a specific sequence by means of the DFT-HF hybrid method at the B3LYP/6-31G(d) level. Only an enantiomer with the same epoxide absolute configuration as that of kapurimycin Ag showed a remarkable G alkylation reactivity with a high selectivity for 5' G of the 5'GG3' sequence, Molecular mechanics calculations suggested that the intercalation of the aglycon model in an orientation perpendicular to neighboring base pairs is essential for the effective G alkylation at 5' G of GN sequences, and the efficiency for G alkylation is not dependent upon the sequence being intercalated. DFT-HF hybrid calculations suggested that the intercalation of the model is energetically most favorable into GG step. These results suggested that highly 5' G selective alkylation of the GG sequence by kapurimycin A(3) arises from a selective intercalation into the GG step. Stacking interaction with both 5' and 3' side Gs is a basis for the stabilization of the intercalated complex.