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 A3 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 A3, 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 A3, 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 A3 showed a remarkable G ...