The Ligand Binding Affinity of an Antitumoral Ru-complex with Calf-Thymus DNA
as Revealed by NMR Spectroscopy

Tiago Venâncio, Department of Chemistry, Laboratory of Nuclear Magnetic Resonance Federal, University of São Carlos, São Carlos, Brazil (t_venancio@yahoo.com)
Flávio Vinícius Crizóstomo Kock, Department of Chemistry, Laboratory of Nuclear Magnetic Resonance, Federal University of São Carlos, São Carlos, Brazil
Analu Rocha Costa, Department of Chemistry, Laboratory of Structure and Reactivity of Inorganic Compounds, Federal University of São Carlos, São Carlos, Brazil.
Alzir Azevedo Batista, Department of Chemistry, Laboratory of Structure and Reactivity of Inorganic Compounds, Federal University of São Carlos, São Carlos, Brazil.
Antônio Gilberto Ferreira, Department of Chemistry, Laboratory of Nuclear Magnetic Resonance, , Federal University of São Carlos, São Carlos, Brazil


Metallodrugs, such as cisplatin and carboplatin, are traditional chemotherapeutics widely used, based on their strong interaction with DNA, possibly destroying its structure, but without selectivity. In this context, the search for other successful and selective metallodrugs plays an important role. Recently, a ruthenium complex, [Ru(law)(dppb)(bipy)] (law = lawsone, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2`-bipyridine), named as CBLAU, was prepared with this purpose. The cytotoxicity for this drug candidate against the tumor cell lines DU-145 (prostate cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells) founds consolidated in literature as well as its potential to induce the tumor cells apoptosis. Therefore, our goal is to bring to light the most accessible interaction sites for this CBLAU Ru-complex towards to calf-thymus DNA (ct-DNA, here selected as the macromolecular target). For this purpose, advanced NMR binding-target approaches, among them Saturation Transfer Difference (STD)-NMR . The results reveal that the aromatic protons exhibit closer proximity to ct-DNA, in comparison with the other types of protons, as expected, given the aromatic character of nitrogen bases. This finding points out that this intermolecular interaction takes place through a spatial π-π stacking. The epitope map shows a shorter contact for dppb, whilst for bipy and lawsone groups this contact are longer. The epitope map obtained for the non-complexed lawsone also shows an efficient intermolecular binding to ct-DNA for the same aromatic protons, reinforcing the relevance of the π-π stacking role on this interaction. Moreover, looking at the binding efficiency, it was observed a stronger interaction (KD = 1.3 mM) for CBLAU/ct-DNA in comparison to individual lawsone/DNA (KD = 128.9 mM). Therefore, this outcome NMR results reveals, at atomic level, the binding affinity interaction for CBLAU towards ct-DNA and provides a guideline for further frontier researchers to search new metallodrugs as chemotherapeutics.

This work is sponsored by FAPESP (2018/09145-5 and 2018/16040-5) and CNPq (455630/2014-3)

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Abstract Reference & Short Personal Biography of Presenting Author

The presenting author, Dr Tiago Venâncio, is Chemist by the University of São Paulo, Brazil, with his PhD in Chemistry at the same university. Recently, he was an academic visitor at The Univesity of Warwick, in the UK, working on high resolution solid state NMR of pharmaceuticals, at Prof. Steven Brown´s group. Currently he is an Associate Professor at Federal University of São Carlos, in Brazil. His main background is Nuclear Magnetic Resonance Spectroscopy, developing high resolution NMR applications to characterize organic and metallo-organic compounds as well as supramolecular complexes in solution and solid state. His group´s research is currently devoted to study supramolecular systems with pharmaceutical interests.