Synthesis of directly linked diazine isosteres of pyrrole-polyamide that photochemically cleave DNA

Abstract

A distamycin model containing an isosteric diazine linked pyrrole has been designed and synthesized. The key steps of the synthesis involved the successful diazotization of the 4-amino-pyrrole derivatives to give the diazomium salts, which undergo coupling reactions with N-methylpyrrole to yield the directly linked diazine compounds. The amide isosteric-diazine pyrrole I demonstrated photo-induced DNA damage upon iradiation with UV light (365 nm). Spectrophotometric and mass spectrometric identification suggest that the azo-linkage in I did not dissociate during irradiation. Moreover, compound I produced DNase I footprints with the HexB DNA fragment at AT sites, as well as some other mixed sequences (5′-ATGTCG-3′), indicative of the additional role of the diazine-linkage for interaction at the duplex DNA.