TriplatinNC and Biomolecules: Building Models Based on Non-covalent Interactions.

Nathália M P Rosa,Luiz Antônio S Costa,Frederico Henrique do C Ferreira,Nicholas P Farrell

doi:10.3389/fchem.2019.00307

Nathália M P Rosa, Luiz Antônio S Costa + Show 2 more

Open Access

https://doi.org/10.3389/fchem.2019.00307

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Abstract

The class of polynuclear platinum(II) compounds have demonstrated a great interest because their high activity against cancer cells. Among these new compounds, the TriplatinNC also called AH78, demonstrated surprising antitumor activity, in some cases equivalent to cisplatin. It is well-known that complex charge +8 favors interaction with DNA and other biomolecules non-covalently, through the hydrogen bonds with phosphate and sulfate groups present in these structures. The hydrogen atoms of the amine interact with the oxygen atoms of the phosphate and sulfate groups present in the DNA strand and heparan sulfate, respectively. These interactions can cause significant twists in double helix and inhibit the activity of these biomolecules. The present investigation is an attempt to provide a benchmark theoretical study about TriplatinNC. We have described the non-covalent interactions through small reliable mimetic models. The non-covalent interactions were also evaluated on larger models containing DNA fractions with six nitrogenous base pairs (CGCGAA) and fractions of the disaccharide that makes the HS evaluated by the hybrid QM/MM ONIOM methodology.

Highlights

Cisplatin has been the most widely metal-based drug used for the treatment of cancer in almost four decades, but the efficacy of this drug has become more difficult because of acquired resistance and severe side effects such as nephrotoxicity, neurotoxicity, and hearing system damage (Wong and Giandomenico, 1999)
It is noted that the arginine-fork structures present the most negative values, suggesting that such structures are more stable than the clamps, for the methodology studied
We analyzed a model that represents the arginine-forks composed of a phosphate group and the amino acid arginine (Figure 5)

Summary

Introduction

Cisplatin has been the most widely metal-based drug used for the treatment of cancer in almost four decades, but the efficacy of this drug has become more difficult because of acquired resistance and severe side effects such as nephrotoxicity, neurotoxicity, and hearing system damage (Wong and Giandomenico, 1999). The searching for new compounds such as polynuclear platinum complexes (PPCs) that show anti-cancer activity have increase in recent years (Mangrum and Farrell, 2010; Prisecaru et al, 2014; Farrell, 2015; Qu et al, 2015). PPCs have shown great promise against cancer cells due to faster and more effective interactions with the DNA when compared to mononuclear complexes because they have more than one platinum core available to coordinate, exhibiting chemical and biological properties that differ significantly to cisplatin (Qu et al, 2004)

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