Electron paramagnetic resonance characterization and conformation of daunorubicin semiquinone intermediate implicated in anthracycline metabolism, cardiotoxicity, and anticancer action

Abstract

The antitumor antibiotic daunorubicin, upon reduction in aqueous solution, gives a transient resolved epr spectrum of linewidth 17.0 G and g value of 2.0024. This is ascribed to the semiquinone previously tentatively assigned in the unresolved epr spectrum obtained by microsomal activation of the antibiotic. By reference to the epr spectrum of quinizarin semiquinone in aqueous solution the individual proton hyperfine splitting constants in both spectra were tentatively assigned by computer simulation. LCAO–MO calculations of one-electron wave function spin densities in both species gave good agreement between calculated and observed hfs for values of the parameters βCO/βCC = 1.8, δα = 1.4, allowing definite assignment of the aromatic protons. By considering the angular dependence of the ring A benzylic proton hfs it was possible to discriminate between two alternative half-chair conformations of daunorubicin semiquinone. The preferred conformation of the intermediate is tentatively assigned as that which places both 7 and 9 oxygen functions equatorial and the C-9 acetyl group axial.