Understanding the ring-opening, chelation and non-chelation reactions between nedaplatin and thiosulfate: a DFT study based on NBO, ETS-NOCV and QTAIM
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The current work investigates a DFT-based in silico study on the mechanism of reaction between the anticancer drug nedaplatin [Pt(NH3)2(Gly-κ2O,O′)] (Gly = –OCCH2COO–) and the rescue agent thiosulfate (S2O3 2−) in molar ratios 1:1 and 1:2, in neutral- and proton-assisted pathways. The first step produces stable (κS or κO) intermediates via ring opening of Gly. The second, rate-limiting step consists of three competing reactions: (1) κ2S,O-chelate formation by S2O3 2− or HS2O3 − (2) Pt-bis(thiosulfate) formation by the elimination of Gly ligand and (3) Pt-bis(thiosulfate) formation by the elimination of one NH3 trans to sulfur owing to strong trans-labilizing thiosulfate ligand. Results show that non-chelation reaction involving uptake of the second thiosulfate is kinetically more favorable than the corresponding κ2S,O-chelate formation. Further, the kinetic barrier of NH3 loss reaction is found to be very close to that of Gly loss. However, in solution phase, the ammine loss reaction is slower than the glycolate loss. The possibility of the formation of four-membered binuclear μ-thiosulfate bridge [Pt2(μ-S2O3)2(NH3)4] has also been considered. The proposed reaction paths have been substantiated through computation of structural, thermodynamic and kinetic parameters involved in the gas and solution phase, and also by topological analysis based on quantum theory of atoms in molecules of Bader and the ETS-NOCV energy decomposition scheme.
KeywordsNedaplatin Cisplatin DNA DFT Kinetic parameters Anticancer drug Thiosulfate
The author is thankful to Professor A. K. Mukherjee for the encouragement and support and especially to Professor J.V. Burda, who helped a lot in this field. The author is grateful to Professor M. Mitoraj for valuable discussion. Helpful suggestions by colleagues Dr. P. K. Chattopadhyay and Dr. N. R. Sinha are also thankfully acknowledged. Finally, the author is also thankful to the reviewer for his thorough and helpful comments.
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