Azinomycin B is a natural product that alkylates DNA by the positioning of reactive epoxide and aziridine moieties in the major groove. The intercalation of a 7-methoxy-1-methylnaphthalene chromophore between the DNA base pairs is crucial binding feature that facilitates the association of the pendant side chain containing the reactive functionality with the major groove. In efforts to create a major-groove binding “staple” ligand, we have synthesized a series of derivatives of the azinomycin chromophore in which two 7-methoxy-1-methylnaphthalene moieties are tethered by diamine linkers of varying lengths. DNA binding studies involving fluorescent intercalator displacement assays and isothermal titration calorimetry have assisted in identifying an optimized linker structure for high affinity DNA binding. The potential advantages of this ligand system over the major groove “staple” drug ditercalinium in terms of the reduced aromatic surface area required for intercalation will be discussed.

Synthesis and DNA binding profile of dimers of the azinomycin chromophore

251st National Meeting (2016)

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