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Insights into Cisplatin Binding to Uracil and Thiouracils from IRMPD Spectroscopy and Tandem Mass Spectrometry

Abstract : The monofunctional primary complexes cis-[PtCl(NH3)2(L)]+, formed by the reaction of cisplatin, a major chemotherapeutic agent, with four nucleobases L, i.e. uracil (U), 2-thiouracil (2SU), 4-thiouracil (4SU) and 2,4-dithiouracil (24dSU), have been studied by a combination of infrared multiple photon dissociation (IRMPD) action spectroscopy, in both the fingerprint (900-1900 cm-1) and the N-H/O-H stretching (3000-3800 cm-1) ranges, energy-resolved collision-induced dissociation (CID) mass spectrometry and by density functional calculations at the B3LYP/LACVP/6-311G** level. On the basis of the comparison across the experimental features and the linear IR spectra of conceivable structures, the cisplatin residue is found to promote a monodentate interaction preferentially with the O4(S4) atoms of the canonical forms of U, 4SU and 24dSU and to the S2 atom of 2SU, yielding the most stable structures. Additional absorptions reveal the presence of minor, alternative tautomers in the sampled ion populations of 2SU and 24dSU, underlying the ability of cisplatin to increase the prospect of (therapeutically beneficial) nucleic acid strand disorder. Implication of these evidences may provide insights into drug mechanism and design.
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Contributor : Jean-Yves Salpin <>
Submitted on : Monday, April 6, 2020 - 3:42:12 PM
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Maria Elisa Crestoni, Davide Corinti, Barbara Chiavarino, Simonetta Fornarini, Debora Scuderi, et al.. Insights into Cisplatin Binding to Uracil and Thiouracils from IRMPD Spectroscopy and Tandem Mass Spectrometry. Journal of The American Society for Mass Spectrometry, Springer Verlag (Germany), 2020, 31 (4), pp.946-960. ⟨10.1021/jasms.0c00006⟩. ⟨hal-02533691⟩



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