HIGHLY SELECTIVE DNA ALKYLATION AT THE 5'-SIDE-G OF A 5'GG3' SEQUENCEBY AN AGLYCON MODEL OF PLURAMYCIN ANTIBIOTICS THROUGH PREFERENTIAL INTERCALATION INTO THE GG-STEP

Altromycin B and kapurimycin Ag are new members of the pluramycin fami ly antibiotics that alkylate N7 of guanine (G) in duplex DNA at an epo xide subunit attached to the C2 position of the pyranone ring. While 5 'AG3' selective alkylation by altromycin B was accounted for by select ive binding to the sequence, it remained uncertain why kapurimycin A(3 ), which is structurally similar to an aglycon part of altromycin B bu t has an epoxide subunit with an opposite absolute configuration, sele ctively alkylates 5' G of the 5'GG3' sequence. To clarify the molecula r basis for the sequence-selective G alkylation by kapurimycin A(3), w e have examined the DNA cleavage sequence selectivity of an enantiomer ic pair of an aglycon model of pluramycin antibiotics and calculated t otal energy change upon intercalation of the model into a specific seq uence 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 t hat of kapurimycin Ag showed a remarkable G alkylation reactivity with a high selectivity for 5' G of the 5'GG3' sequence, Molecular mechani cs 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 effic iency for G alkylation is not dependent upon the sequence being interc alated. 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 st ep. Stacking interaction with both 5' and 3' side Gs is a basis for th e stabilization of the intercalated complex.