A DFT study of reactions of Ru(III) anticancer drug KP1019 with 8-oxoguanine and 8-oxoadenine
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ORIGINAL RESEARCH
A DFT study of reactions of Ru(III) anticancer drug KP1019 with 8-oxoguanine and 8-oxoadenine Pramod Kumar Shah 1 & P. K. Shukla 1 Received: 28 February 2020 / Accepted: 3 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The cytotoxic activities of KP1019 and other Ru(III) drugs are believed to be associated with their binding with DNA. Here, we report the density functional theory (DFT) study of reactions of KP1019 drug at the O6 and O8 sites of 8-oxoguanine (8-oxoG) and the O8 site of 8-oxoadenine (8-oxoA). 8-OxoG is predominantly formed in oxidative stress and can cause mutation and cancer. It is found that the barrier free energies (ΔGb) of these reactions obey the following trend: O8 (8-oxoG) < O8 (8-oxoA) < O6 (8-oxoG), at different levels of theory in gas phase and aqueous media. The ΔGb of reaction at the O8 (8-oxoG) is found to be 10.96 (13.81) kcal/mol at the M06-2X/(LanL2DZ+6-311+G**) level of theory in gas phase (aqueous media). The rate constant of reaction at the O8 (8-oxoG) site in aqueous media is 4.6 × 102 s−1. The reaction free energies (ΔGf) and reaction enthalpies (ΔHf) of all the reactions are appreciably negative in both gas phase and aqueous media which indicate that the reaction of monoaquated KP1019 at the O6 and O8 sites of 8-oxoG as well as at the O8 site of 8-oxoA would occur spontaneously. Further, our calculations demonstrate that KP1019 would react with 8-oxoG more favourably as compared with guanine. Thus, it predicts that the main mechanism of the action of KP1019 drug might be due to its binding with the O8 site of 8-oxoG in biological media. Keywords DNA damage . Ru anticancer drugs . NAMI-A . KP1019 . 8-oxoguanine . Cancer
Introduction Ruthenium (Ru) anticancer drugs have the potential to be used as an alternative to the platinum (Pt) drugs which are predominant drugs in the treatment of various types of cancer [1, 2]. Therefore, the synthesis, structure, and properties of Ru drugs as well as their mechanisms of action including interactions with potential biological targets have been the subject of several investigations [3–12]. It is considered that Ru(III) drugs, before binding to different biomolecules in vivo, are activated via two mechanisms: hydrolysis and reduction [2, 11, 13]. It is very recently found using density functional theory (DFT) calculations that axial ligands play an important role in the hydrolysis of Ru(III) complexes similar to NAMI-A [12]. The cytotoxic activities of Ru drugs are attributed to their binding with DNA [14–18]. In DNA, Ru drugs bind largely with the N7 site of guanine [16, 19, 20]. However, their bindings with other DNA bases such as adenine and cytosine have * P. K. Shukla [email protected]; [email protected] 1
Department of Physics, Assam University, Silchar 788011, India
also been observed [5, 19, 20]. It is reported that Ru drugs can also yield DNA interstrand crosslinks or induce strand breaks [18]. Beside DNA, Ru drugs can also interact and bind with various pr
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