Nonclassic Metallointercalators with Dipyridophenazine: DNA Interaction Studies and Leishmanicidal Activity

Abstract

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.

Octahedral ruthenium (II) polypyridyl complexes as antimicrobial agents against mycobacterium

“…Due to the success of cis -platinum anticancer agents, there has been considerable interest in the development of therapeutic agents based upon other transition metals and ruthenium(II) complexes in particular, because of their well known interaction with nucleic acids, which are generally believed to be a target for many metal-based drugs (Abid, Shamsi & Azam, 2016; Madureira et al, 2013). Octahedral ruthenium complexes have shown tremendous applications in different areas of biological research (Kostova, 2006; Li, Collins & Keene, 2015).…”

Synthesis and the characterization of Schiff-base copper complexes: Reactivity with DNA, 4-NPP and BNPP

“…Several other phen and related ligands have been coordinated to copper and studied. A significant number of the complexes have been found to exhibit reactivity similar to nucleases [60][61][62][63][64]. Whereas the phen and related ligands have seen more frequent applications, other planar pi systems like quinoline have attracted less attention [65,66].…”

Ratiometric Quantum Dot–Ligand System Made by Phase Transfer for Visual Detection of Double-Stranded DNA and Single-Nucleotide Polymorphism

“…The dppz attachment was confirmed by FT-IR measurements (Figure S1 in the Supporting Information). Characteristic vibration bands from dppz (740.6, 1490.7 cm –1 for benzene ring; 1637 cm –1 for nitrogen heterocycle) appear in the spectra of the QD–L sensor instead of the QDs nanohybrid . In this sensor, dppz acts as the gQDs ligand, which was confirmed by XPS measurements, and the results are shown in Figure D.…”