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 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 evidence may provide insights into drug mechanism and design.