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Understanding the interaction of an antitumoral platinum(II) 7-azaindolate complex with proteins and DNA

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Abstract

The reactivity of the [Pt(dmba)(aza-N1)(dmso)] complex 1, (a potential antitumoral drug with lower IC50 than cisplatin in several tumoral cell lines) with different proteins and oligonucleotides is investigated by means of mass spectrometry (ESI-TOF MS). The results obtained show a particular binding behaviour of this platinum(II) complex. The interaction of 1 with the assayed proteins apparently takes place by Pt-binding to the most accessible coordinating amino acids, presumably at the surface of the protein -this avoiding protein denaturation or degradation- with the subsequent release of one or two ligands of 1. The specific reactivity of 1 with distinct proteins allows to conclude that the substituted initial ligand (dmso or azaindolate) is indicative of the nature of the protein donor atom finally bound to the platinum(II) centre, i.e. N- or S-donor amino acid. Molecular modeling calculations suggest that the release of the azaindolate ligand is promoted by a proton transfer to the non-coordinating N present in the azaindolate ring, while the release of the dmso ligand is mainly favoured by the binding of a deprotonated Cys. The interaction of complex 1 with DNA takes always place through the release of the azaindolate ligand. Interestingly, the interaction of 1 with DNA only proceeds when the oligonucleotides are annealed forming a double strand. Complex 1 is also capable to displace ethidium bromide from DNA and it also weakly binds to DNA at the minor groove, as shown by Hoechst 33258 displacement experiments. Furthermore, complex 1 is also a good inhibitor of cathepsin B (an enzyme implicated in a number of cancer related events). Therefore, although compound 1 is definitely able to bind proteins that can hamper its arrival to the nuclear target, it should be taken into consideration as a putative anticancer drug due to its strong interaction with oligonucleotides and its effective inhibition of cat B.

Graphical Abstract

Reactivity of a Pt complex: The interaction of a potential antitumoral drug, [Pt(dmba)(aza-N1)(dmso)], with distinct proteins and oligonucleotides has been studied by means of ESI-TOF MS. The particular reactivity of this complex in front of the assayed biomolecules required the use of spectroscopic techniques and theoretical calculations to elucidate its mechanism. This information will contribute to its consideration as a putative anticancer drug.

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Abbreviations

aza:

7-Azaindolate

cat B:

Cathepsin B

Cyt C:

Cytochrome C

Dmba:

N,N-dimethylbenzylamine-κN,κC

Dmso:

Dimethylsulfoxide

DS:

Double strand oligonucleotide

EB:

Ethidium bromide

HSA:

Human serum albumin

MT1:

Zn7-MT complex of the recombinant mouse metallothionein isoform 1

Myo:

Myoglobin

SS:

Single strand oligonucleotide

Tf:

Transferrin

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Acknowledgments

This work was supported by the Spanish Ministerio de Ciencia e Innovación and FEDER through the following projects: SAF2011-26611 to J. Ruiz, BIO2012-39682-C02-01 to S. Atrian, and BIO2012-39682-C02-02 to M. Capdevila; CTQ2008-06866-C02-01 and consolider-ingenio 2010 to J.-D. Marechal. J. Ruiz also acknowledges the financial support received from Fundación Seneca-CARM (Project 08666/PI/08). The authors from UAB and UB are members of the Grup de Recerca de la Generalitat de Catalunya refs. 2009SGR-1457 and 2009SGR-68. S. Artime, at S. Atrian’s lab, was responsible of the recombinant synthesis of Zn7-MT1.

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Authors and Affiliations

  1. Departament de Química, Facultat de Ciències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, 08193, Barcelona, Spain

    Katia G. Samper, Elisabeth Ortega-Carrasco, Jean Didier Maréchal, Mercè Capdevila & Òscar Palacios

  2. Departamento de Química Inorgánica, Universidad de Murcia, 30071, Murcia, Spain

    Venancio Rodríguez, Natalia Cutillas, Ana Zamora, Concepción de Haro & José Ruiz

  3. Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain

    Venancio Rodríguez, Natalia Cutillas, Ana Zamora, Concepción de Haro & José Ruiz

  4. Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, 08028, Barcelona, Spain

    Sílvia Atrian

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  1. Katia G. Samper
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  2. Venancio Rodríguez
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  9. Mercè Capdevila
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Correspondence to Òscar Palacios.

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Samper, K.G., Rodríguez, V., Ortega-Carrasco, E. et al. Understanding the interaction of an antitumoral platinum(II) 7-azaindolate complex with proteins and DNA. Biometals 27, 1159–1177 (2014). https://doi.org/10.1007/s10534-014-9780-1

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