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Nonclassic Metallointercalators with Dipyridophenazine: DNA Interaction Studies and Leishmanicidal Activity

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Department of Chemistry, Virginia Commonwealth University, 1001 West Main Street, Richmond, Virginia 23284, United States
Departamento de Química e Bioquímica, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Departamento de Química, Universidade de Aveiro, Campus de Santiago, 3810-193 Aveiro, Portugal
Unidade de Parasitologia Médica, #Centro de Malária e outras Doenças Tropicais, and &Unidade de Saúde Pública Internacional e Bioestatística, Instituto Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa (UNL), Rua da Junqueira 100, 1349-008 Lisboa, Portugal
% Departamento Ciências Biomédicas e Medicina, Universidade do Algarve, Campus de Gambelas, 8000-117 Faro, Portugal
Cite this: Inorg. Chem. 2013, 52, 15, 8881–8894
Publication Date (Web):July 11, 2013
Copyright © 2013 American Chemical Society

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    Complexes [Cu(CH3COO)(dppz)2]CH3COO (1) and [Zn(dppz)2](BF4)2 (2) with the intercalator dipyridophenazine (dppz) were prepared to obtain metallointercalators with increased geometrical flexibility compared to octahedral ones. Biophysical results (thermal denaturation, circular dichroism, rheometry, atomic force microscopy) indicate a strong interaction with DNA by intercalation and the existence of a positive cooperative effect with groove binding being preferred at low concentration of complexes. Induced circular dichroism (ICD) studies with DNA show that compounds 1 and 2 have a preferred orientation when binding to DNA. Since the compounds lack functional groups to permit hydrogen bonds, a combined intercalation/covalent binding mode is plausible. Further studies by QTof-ESI-MS and tandem experiments with GC oligonucleotides strongly support this dual-binding mode, since binding requires loss of one dppz unit with the copper center remaining attached to DNA even after another dppz loss. DNA saturation by the copper compound occurs at about one-half the concentration required for the zinc complex. Molecular modeling results suggest that it is caused by the increased ability of Cu(II) to distort to a more planar structure during interaction with DNA. Compounds 1 and 2 are active against a viscerotropic Leishmania infantum strain at submicromolar concentrations (IC50 = 0.57 and 0.46 μM, respectively), being more active than the reference drug miltefosine (M) (15.97 μM). They are also more cytotoxic than the control on human macrophages (MTD25 = 0.41 (1), 0.63 (2)). Besides miltefosine, the zinc compound is the only one with a MTD25/IC50 ratio above 1 on the promastigote phase (1.39) and was further studied on the amastigote form with a significant improvement in the therapeutic index (2.51). Combined analysis of DNA biophysical studies, parasite activity, and cytotoxicity measurements suggests that intercalation correlates with leishmanicidal activity, while cytotoxicity results are justified by a combination of DNA intercalation and possible radical formation in the case of Cu(II), most probably hydroxyl and/or singlet oxygen radicals.

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    Spectroscopic characterization of complexes (infrared and UV–vis), thermal denaturation, AFM images, and ESI-MS studies of complexes:DNA interactions, generalized additive model charts of macrophages and parasite cells viability, and coordinates of energy-minimized structure of the complexes. This material is available free of charge via the Internet at

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