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

Davide Corinti,Barbara Chiavarino,Jean-Yves Salpin,Debora Scuderi,Simonetta Fornarini,Maria Elisa Crestoni

doi:10.1021/jasms.0c00006

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.

Highlights

In spite of their peculiar biological properties, only a few theoretical and experimental studies dedicated to the structural characterization of thiouracils at the molecular level were available at the end of the 1980s
Thiouracils have been identified as minor components of transfer-RNA,[1] and the existence of these molecules in many tautomeric forms, like for other nucleobases, seems to be a key point to account for the mistranslation of genetic information.[2−4] this feature has motivated both theoretical and experimental studies on tautomeric equilibria of nucleobases and thiobases in order to establish a relationship between the presence of enol tautomeric forms and the appearance of point mutations during DNA replication.[5−16] In addition, thiouracils exhibit many interesting therapeutic applications for antithyroid,[17,18] antiviral,[19,20] anticancer,[21,22] and heart disease[23,24] therapies
Infrared multiple photon dissociation (IRMPD) spectroscopy has been applied to the characterization of protonated and sodiated uracil and thiouracils complexes,[15,32,33] disclosing that protonation preferentially stabilizes alternative, noncanonical tautomers of uracil and of all the thiouracils aside from 4-thiouracil (4SU), whereas the sodium cation binds to the canonical tautomers of uracil (U) and 2-thiouracil (2SU), and to minor tautomers of 4-thiouracil (4SU) and 2,4-thiouracil (24SU)

Summary

■ INTRODUCTION

In spite of their peculiar biological properties, only a few theoretical and experimental studies dedicated to the structural characterization of thiouracils at the molecular level were available at the end of the 1980s. According to the computational analysis that points to a coordination scheme governed by the distinct contribution of a zwitterionic effect and the strong cisPt affinity for sulfur, different types of structures are likely to be present in the sampled ion population, depending on the number of sulfur atoms This notion is consistent with the experimental findings by IRMPD spectroscopy (Figure 2), both in the fingerprint and the X-H stretch regions. The interaction of cisPt with 24dSU likely originates a mixture of different forms, the canonical S4-coordinated complexes being largely the most populated

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES