title: Determination of phenolic ionization constants of anthracyclines with modified substitution pattern of anthraquinone chromophore.
abstract: The phenolic ionization constants in aqueous solution of doxorubicin, daunorubicin and nine daunorubicin analogues with different substitution patterns at the anthraquinone moiety have been determined spectrophotometrically upon taking into account aggregation effects with extrapolation to infinite dilution. In contrast with an early literature report [Sturgeon, R.J. & Schulman, S.G. J. Pharm. Sci. 66, 958-961; 1977] the perturbation from amino group ionization on daunosamine sugar was found to be negligible in our spectrophotometric titrations. Accordingly, only phenol hydroxyl ionization constants could be determined in these experiments, but a crude estimate of daunosamine pKa was obtained in a fluorometric titration. From a comparison of suitable analogues it is concluded that the phenolic function at C11 in doxorubicin and daunorubicin is the most acidic one. The higher pKa of the C6-OH group is ascribed in part to electronic effects leading to higher strength of the corresponding hydrogen bond with quinone oxygen, and in part to a steric effect from the bulky sugar group at C7. Ionization constants of nitro or amino substituted derivatives follow the expected trend. In the cases of carminomycin and 6-deoxycarminomycin, which both have another phenolic group at C4, two phenolic ionization processes can be detected in the experimentally accessible pH range (5-12): these are ascribed to C4-OH and C11-OH. An application of the compiled parameters to studies of chemical reactivity and biological activity of anthracyclines is foreseen.
authors: Famitalia Carlo Erba srl, Erbamont Group Research & Development, Milan, Italy.
authors: G
authors: G
authors: Razzano
authors: V
authors: V
authors: Rizzo
authors: A
authors: A
authors: Vigevani
mesh_terms: D000880:Anthraquinones / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D002360:Carubicin / Q000737:chemistry; D003630:Daunorubicin / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry; D007700:Kinetics; D010636:Phenols / Q000737:chemistry*; D013050:Spectrometry, Fluorescence
chemical_list: D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D010636:Phenols; D004317:Doxorubicin; D002360:Carubicin; D003630:Daunorubicin