Pulse radiolysis studies on the formation and transformation of the one-electron reduced intermediate of Kalafungin and an analogue solution

Kalafungin 1 is a member of the pyranonaphthoquinone family of antibiotics which are produced various species of Streptomyces and have in common the benzoisochromanquinone skeleton. Apart from their already documented activity against Gram-positive bacteria, fungi, and mycoplasmas, it has been suggested that in vivo reduction causes a transformation to an active hydroquinone form which functions as a bis-alkylating agent.2 Moore2,3 has suggested that these pyranonaphthoquinones may exhibit antitumour activity since the proposed mechanism of action resembles that of the anticancer agent mitomycin C 3.2. Rapid one-electron reduction of kalafungin 1 and a closely related analogue 2 has been carried out using The University of Auckland's pulse radiolysis facility. Pulsed electrons (4 Gy in 200 ns from a 4 MeV linear accelerator) were delivered to de-aerated aqueous solutions (10 mmol.L-1 phosphate, pH 7.0) containing 0.1 mol.L-1 sodium formate and 50 - 200 μmol.L-1 kalafungin 1 or lactol 2. Radical formation and transformations were followed by time-resolved uv/visible spectrophotometry. The transformations observed are independent of both the concentration of the parent compound and radiation doses (i.e. semiquinone concentration). The accompanying changes in absorption are consistent with the radical centre of the semiquinone species undergoing intramolecular rearrangement onto the fused non-aromatic ring structure of the compound. Possible ring opening mechanisms and the position of radical relocalisation will be discussed, as well as the involvement of radical transformation and redox chemistry in the biological activity of kalafungin1