Heterocyclic dithiocarbazate iron chelators: Fe coordination chemistry and biological activity

The iron coordination and biological chemistry of a series of heterocyclic dithiocarbazate Schiff base ligands is reported with regard to their activity as Fe chelators for the treatment of Fe overload and also cancer. The ligands are analogous to tridentate heterocyclic hydrazone and thiosemicarbazone chelators we have studied previously which bear NNO and NNS donor sets. The dithiocarbazate Schiff base ligands in this work also are NNS chelators and form stable low spin ferric and ferrous complexes and both have been isolated. In addition an unusual hydroxylated ligand derivative has been identified via an Fe-induced oxidation reaction. X-ray crystallographic and spectroscopic characterisation of these complexes has been carried out and also the electrochemical properties have been investigated. All Fe complexes exhibit totally reversible Fe couples in mixed aqueous solvents at potentials higher than found in analogous thiosemicarbazone Fe complexes. The ability of the dithiocarbazate Schiff base ligands to mobilise Fe from cells and also to prevent Fe uptake from transferrin was examined and all ligands were effective in chelating intracellular Fe relative to known controls such as the clinically important Fe chelator desferrioxamine. The Schiff base ligands derived from 2-pyridinecarbaldehyde were non-toxic to SK-N-MC neuroepithelioma (cancer) cells but those derived from the ketones 2-acetylpyridine and di-2-pyridyl ketone exhibited significant antiproliferative activity

Kinetico-mechanistic studies on methemoglobin generation by biologically active thiosemicarbazone iron(III) complexes

The oxidation of human oxyhemoglobin (HbO) to methemoglobin (metHb) is an undesirable side effect identified in some promising thiosemicarbazone anti-cancer drugs. This is attributable to oxidation reactions driven by Fe complexes of these drugs formed in vivo. In this work the Fe complexes of selected 2-benzoylpyridine thiosemicarbazones (HBpT), 2-acetylpyridine thiosemicarbazones (HApT), and the clinically trialled thiosemicarbazone, Triapine® (3-amino-2-pyridinecarboxaldehyde thiosemicarbazone, H3-AP), have been studied. This was achieved by time-resolved UV–Visible absorption spectroscopy and the sequential oxidation of the α- and β-chains of HbO at distinctly different rates has been identified. A key structural element, namely a terminal –NH group on the thiosemicarbazone moiety, was found to be an important common feature of the most active HbO oxidising complexes that were investigated. Therefore, these studies indicate that an unsubstituted –NH moiety at the terminus of the thiosemicarbazone group should be avoided in the design of future compounds from this class

Synthesis, Characterization, DFT Studies of Novel Cu(II), Zn(II), VO(II), Cr(III), and La(III) Chloro-Substituted Schiff Base Complexes: Aspects of Its Antimicrobial, Antioxidant, Anti-Inflammatory, and Photodegradation of Methylene Blue

A new chlorobenzylidene imine ligand, (E)-1-((5-chloro-2-hydroxybenzylidene)amino) naphthalen-2-ol (HL), and its [Zn(L)(NO3)(H2O)3], [La(L)(NO3)2(H2O)2], [VO(L)(OC2H5)(H2O)2], [Cu(L)(NO3)(H2O)3], and [Cr(L)(NO3)2(H2O)2], complexes were synthesized and characterized. The characterization involved elemental analysis, FT-IR, UV/Vis, NMR, mass spectra, molar conductance, and magnetic susceptibility measurements. The obtained data confirmed the octahedral geometrical structures of all metal complexes, while the [VO(L)(OC2H5)(H2O)2] complex exhibited a distorted square pyramidal structure. The complexes were found to be thermally stable based on their kinetic parameters determined using the Coats–Redfern method. The DFT/B3LYP technique was employed to calculate the optimized structures, energy gaps, and other important theoretical descriptors of the complexes. In vitro antibacterial assays were conducted to evaluate the complexes’ potential against pathogenic bacteria and fungi, comparing them to the free ligand. The compounds exhibited excellent fungicidal activity against Candida albicans ATCC: 10231 (C. albicans) and Aspergillus negar ATCC: 16404 (A. negar), with inhibition zones of HL, [Zn(L)(NO3)(H2O)3], and [La(L)(NO3)2(H2O)2] three times higher than that of the Nystatin antibiotic. The DNA binding affinity of the metal complexes and their ligand was investigated using UV-visible, viscosity, and gel electrophoresis methods, suggesting an intercalative binding mode. The absorption studies yielded Kb values ranging from 4.40 × 105 to 7.30 × 105 M−1, indicating high binding strength to DNA comparable to ethidium bromide (value 107 M−1). Additionally, the antioxidant activity of all complexes was measured and compared to vitamin C. The anti-inflammatory efficacy of the ligand and its metal complexes was evaluated, revealing that [Cu(L)(NO3)(H2O)3] exhibited the most effective activity compared to ibuprofen. Molecular docking studies were conducted to explore the binding nature and affinity of the synthesized compounds with the receptor of Candida albicans oxidoreductase/oxidoreductase INHIBITOR (PDB ID: 5V5Z). Overall, the combined findings of this work demonstrate the potential of these new compounds as efficient fungicidal and anti-inflammatory agents. Furthermore, the photocatalytic effect of the Cu(II) Schiff base complex/GO was examined

Novel second-generation Di-2-Pyridylketone Thiosemicarbazones show synergism with standard chemotherapeutics and demonstrate potent activity against lung cancer xenografts after oral and intravenous administration in vivo

We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyr-idine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl], identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex

Novel Second-Generation Di-2-Pyridylketone Thiosemicarbazones Show Synergism with Standard Chemotherapeutics and Demonstrate Potent Activity against Lung Cancer Xenografts after Oral and Intravenous Administration in Vivo

We developed a series of second-generation di-2-pyridyl ketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands to improve the efficacy and safety profile of these potential antitumor agents. Two novel DpT analogues, Dp4e4mT and DpC, exhibited pronounced and selective activity against human lung cancer xenografts in vivo via the intravenous and oral routes. Importantly, these analogues did not induce the cardiotoxicity observed at high nonoptimal doses of the first-generation DpT analogue, Dp44mT. The Cu­(II) complexes of these ligands exhibited potent antiproliferative activity having redox potentials in a range accessible to biological reductants. The activity of the copper complexes of Dp4e4mT and DpC against lung cancer cells was synergistic in combination with gemcitabine or cisplatin. It was demonstrated by EPR spectroscopy that dimeric copper compounds of the type [CuLCl]₂, identified crystallographically, dissociate in solution to give monomeric 1:1 Cu:ligand complexes. These monomers represent the biologically active form of the complex

Maintaining Intruder Detection Capability in a Rectangular Domain with Sensors

In order to detect intruders that attempt to pass through a rectangular domain, sensors are placed at nodes of a regular spaced grid laid out over the rectangle. An intruder that steps within the sensing range of a sensor will be detected. It is desired that we prevent potential attacks in either one-dimension or two-dimensions. A one-dimensional attack succeeds when an intruder enters from the top (North) side and exits out the bottom (South) side of the domain without being detected. Preventing attacks in two dimensions requires that we simultaneously prevent the intruder from either entering North and exiting South or entering East (left side) and exiting West (right side) undetected. Initially, all of the sensors are working properly and the domain is fully protected, i.e., attacks will be detected, in both dimensions (assuming the grid points are such that neighboring sensors have overlapping sens- ing ranges and include all four boundaries of the domain). Over time, the sensors may fail and we are left with a subset of working sensors. Under these conditions we wish to (1) determine if one or two-dimensional at- tack detection still persists and (2) if not, restore protection by adding the least number of sensors required to ensure detection in either one or two dimensions. Ideally, the set of currently working sensors would provide some amount of fault-tolerance. In particular, it would be advantageous if for a given k, the set of sensors maintains protection (in one or two-dimensions) even if up to k of the sensors fail. This leads to the problems of (1) deciding if a subset of the sensors provides protection with up to k faults and (2) if not, finding the minimum number of grid points to add sensors to in order to achieve k fault-tolerance. In this paper, we provide algorithms for deciding if a set sensors provides k-fault tolerant protection against attacks in both one and two dimen- sions, for optimally restoring k-fault tolerant protection in one dimension and for restoring protection in two dimensions (optimally for k = 0 and approximately otherwise)

Kinetic studies on the oxidation of oxyhemoglobin by biologically active iron thiosemicarbazone complexes: relevance to iron-chelator-induced methemoglobinemia

The oxidation of oxyhemoglobin to methemoglobin has been found to be facilitated by low molecular weight iron(III) thiosemicarbazone complexes. This deleterious reaction, which produces hemoglobin protein units unable to bind dioxygen and occurs during the administration of iron chelators such as the well-known 3-aminopyridine-2-pyridine-carbaldehyde thiosemicarbazone (3-AP; Triapine), has been observed in the reaction with Fe complexes of some members of the 3-AP structurally-related thiosemicarbazone ligands derived from di-2-pyridyl ketone (HDpxxT series). We have studied the kinetics of this oxidation reaction in vitro using human hemoglobin and found that the reaction proceeds with two distinct time-resolved steps. These have been associated with sequential oxidation of the two different oxyheme cofactors in the α and β protein chains. Unexpected steric and hydrogen-bonding effects on the Fe complexes appear to be the responsible for the observed differences in the reaction rate across the series of HDpxxT ligand complexes used in this study