The interactions of Fe 3+ ions with adriamycin studied by 57Fe Mossbauer and electronic spectroscopies

The interactions between ferric ions and the anticancer antibiotic adriamycin have been investigated by Fe-57 Mossbauer and electronic spectroscopies. The Mossbauer parameters are markedly dependent on the preparation procedure, the equilibration time, the metal-to-ligand ratio, and the concentration of the drag. At millimolar drag concentration, the 4.2 K Mossbauer spectra exhibit a broad Fe(III) magnetic sextet attributed to polynuclear aggregates of high magnetic anisotropy, and a quadrupole split Fe(III) doublet attributed to a species of lower magnetic anisotropy, which exhibits superparamagnetic behavior. The two species are in equilibrium, as indicated by the time evolution of both Mossbauer and electronic spectra. At 3.0 10(-5) M drag concentration, when adriamycin is mainly monomeric, the 4.2 K Mossbauer spectra exhibit a quadrupole split doublet, connected with a superparamagnetic system, as for the concentrated preparations, and a broad magnetic sextet whose relative area increases with aging. The species responsible for this sextet should be some polymerizable hydrolysis product of the Fe(III) ions present in the dilate solation. In addition, the presence of a transient Fe(II) quadrupole doublet, both in this preparation and when the [Fe]/[ADR] ratio is 1:5 at millimolar drag concentration, is explained with the known intramolecular one-electron redox reaction which ferric-adriamycin undergoes under anaerobic conditions. The present results confirm that adriamycin is markedly more reactive than daunomycin due to its hydroxymethyl side-chain, and suggest that the stacking of the drug molecules plays a role in the observed cooperative phenomena

2-(2-thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: Discovery, SAR, modeling, and mutagenesis

Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2- thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 \u3bcM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions