Interaction of the antitumor antibiotic streptonigrin with metal ions and DNA

Abstract

Streptonigrin is a functionalized 7-aminoquinoline-5,8-dione that is highly active against a range of human cancers. While streptonigrin was in clinical use until 1977, the mechanism of antitumor action of the drug was only investigated in detail after clinical trials were discontinued. In common with other aminoquinone antitumor antibiotics, extensive studies suggest that streptonigrin exerts its antitumor activity by causing DNA strand scission. Metal ions were identified as serving a key role in both the DNA-degradation pathway, either by direct complexation with streptonigrin or reduced streptonigrin and/or catalysing the production of the DNA damaging species, and in enhancing the interaction of the drug with ccc-DNA and calf thymus DNA. While streptonigrin itself interacts only very weakly with DNA, this interaction is strongly enhanced when the drug is reductively activated or in the presence of transition metal ions. This review will cover the literature reported since 1985. Important results that have been recently reported include the solution conformation of the drug, structures of the metal complexes of streptonigrin, characterisation of streptonigrin semiquinone, DNA-footprinting and key structure-activity studies. These reports have clarified some of the mechanistic aspects of streptonigrin-mediated DNA cleavage and provide a basis for rational drug design of streptonigrin analogues with modified therapeutic properties and side effects.