Pt(II)-based derivatives bearing a cyanocobalamin (CNCbI) unit were synthesized in aqueous solutions, and the reaction mixtures were examined by reversed-phase liquid chromatography with electrospray ionization and linear ion trap mass spectrometry (MS). Isotopic pattern analysis, multistage mass-spectra (MS/MS and MS3) interpretation, and differential isotopic labeling were used to establish the chemical composition and to suggest the chemical structures of reaction products. When cisplatin (cis-[PtCl2(NH3)(2)]) was used as a Pt(II) drug,derivative, a coordination bond between diamminemonochloroplatinum(II) and the cyano group of CNCbI, in turn linked covalently to the vitamin Co (III) ion, occurred.. The resulting conjugate with a Co-III-CN-Pt-II bridge was MS detected as a doubly, positive charged ion with the prevailing isotopologue at m/z 810.26 (empirical formula [(C63H95ClCoN16O14PPt)-N-III](2+)). Likewise, a peak signal centered at m/z 811.26 was observed when N-15-labeled cisplatin cis-[PtC12(15NH3)2] PtCl2((NH3)-N-15)(2) was used as Pt(II) complex, thus confirming the presence of both the cisplatin amino groups in the conjugate. A bifunctional conjugate was obtained between CNCbI and the cis-diamminediaquaplatinum(II), that is, cis-[Pt(NH3)(2)(H2O)(2)](2+); in this case, the planar coordination complex of Pt(II) was also involved in a covalent bond with the oxygen atom of one of the CNCbI amide moieties. The peak signal detected at m/z 792.26 (empirical formula [(C63H94CoN16O14PPt)-N-III](2+)) changed to m/z 793.26 when the labeled cis-[Pt((NH3)-N-15)(2)(H2O)(2)](2+) complex was adopted for conjugation. Comparison between MS/MS spectra allowed an extended structural characterization of both conjugates, as such or N-15-labeled. Two-dimensional heteronuclear (H-1-N-15) single quantum correlation NMR spectroscopy, applied to N-15-labeled conjugates, supported the hypotheses made on the Pt(II) coordination in both cases.

Structural Elucidation of Cisplatin and Hydrated cis-Diammineplatinum(II) Complex Conjugated with Cyanocobalamin by Liquid Chromatography with Electrospray Ionization–Mass Spectrometry and Multistage Mass Spectrometry

Ventura, Giovanni;Nardella, Maria Incoronata;Panella, Andrea;Arnesano, Fabio;Calvano, Cosima Damiana;Losito, Ilario;Palmisano, Francesco;Cataldi, Tommaso R. I.
2018

Abstract

Pt(II)-based derivatives bearing a cyanocobalamin (CNCbI) unit were synthesized in aqueous solutions, and the reaction mixtures were examined by reversed-phase liquid chromatography with electrospray ionization and linear ion trap mass spectrometry (MS). Isotopic pattern analysis, multistage mass-spectra (MS/MS and MS3) interpretation, and differential isotopic labeling were used to establish the chemical composition and to suggest the chemical structures of reaction products. When cisplatin (cis-[PtCl2(NH3)(2)]) was used as a Pt(II) drug,derivative, a coordination bond between diamminemonochloroplatinum(II) and the cyano group of CNCbI, in turn linked covalently to the vitamin Co (III) ion, occurred.. The resulting conjugate with a Co-III-CN-Pt-II bridge was MS detected as a doubly, positive charged ion with the prevailing isotopologue at m/z 810.26 (empirical formula [(C63H95ClCoN16O14PPt)-N-III](2+)). Likewise, a peak signal centered at m/z 811.26 was observed when N-15-labeled cisplatin cis-[PtC12(15NH3)2] PtCl2((NH3)-N-15)(2) was used as Pt(II) complex, thus confirming the presence of both the cisplatin amino groups in the conjugate. A bifunctional conjugate was obtained between CNCbI and the cis-diamminediaquaplatinum(II), that is, cis-[Pt(NH3)(2)(H2O)(2)](2+); in this case, the planar coordination complex of Pt(II) was also involved in a covalent bond with the oxygen atom of one of the CNCbI amide moieties. The peak signal detected at m/z 792.26 (empirical formula [(C63H94CoN16O14PPt)-N-III](2+)) changed to m/z 793.26 when the labeled cis-[Pt((NH3)-N-15)(2)(H2O)(2)](2+) complex was adopted for conjugation. Comparison between MS/MS spectra allowed an extended structural characterization of both conjugates, as such or N-15-labeled. Two-dimensional heteronuclear (H-1-N-15) single quantum correlation NMR spectroscopy, applied to N-15-labeled conjugates, supported the hypotheses made on the Pt(II) coordination in both cases.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11586/224855
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