Macrocyclic Copper(II) Complexes as Catalysts for Electrochemically Mediated Atom Transfer

Copper-catalyzed electrochemical atom transfer radical addition (eATRA) is a new method for the creation of new C–C bonds under mild conditions. In this work, we have explored the reactivity of an analogous series of N4 macrocyclic CuII complexes as eATRA precatalysts, which are primed by reduction to their monovalent oxidation state. These complexes were fully characterized structurally, spectroscopically, and electrochemically. A spectrum of radical activation reactivity was found across the series [CuI(Me4cyclen)(NCMe)]+ (Me4cyclen = 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane), [CuI(Me4cyclam)(NCMe)]+ (Me4cyclam = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), and [CuI(Me2py2clen)(NCMe)]+ (Me2py2clen = 3,7-dimethyl-3,7-diaza-1,5(2,6)-dipyridinacyclo-octaphane). The rate of radical production by [Cu(Me2py2clen)(NCMe)]+ was modest, but rapid radical capture to form the organocopper complex [CuI(Me2py2clen)(CH2CN)] led to a dramatic acceleration in catalysis, greater than seen in any comparable Cu complex, but this led to rapid radical self-termination instead of radical addition

Electrocatalytic Atom Transfer Radical Addition with Turbocharged Organocopper(II) Complexes

The utility and scope of Cu-catalyzed halogen atom transfer chemistry have been exploited in the fields of atom transfer radical polymerization and atom transfer radical addition, where the metal plays a key role in radical formation and minimizing unwanted side reactions. We have shown that electrochemistry can be employed to modulate the reactivity of the Cu catalyst between its active (CuI) and dormant (CuII) states in a variety of ligand systems. In this work, a macrocyclic pyridinophane ligand (L1) was utilized, which can break the C–Br bond of BrCH2CN to release •CH2CN radicals when in complex with CuI. Moreover, the [CuI(L1)]+ complex can capture the •CH2CN radical to form a new species [CuII(L1)(CH2CN)]+ in situ that, on reduction, exhibits halogen atom transfer reactivity 3 orders of magnitude greater than its parent complex [CuI(L1)]+. This unprecedented rate acceleration has been identified by electrochemistry, successfully reproduced by simulation, and exploited in a Cu-catalyzed bulk electrosynthesis where [CuII(L1)(CH2CN)]+ participates as a radical donor in the atom transfer radical addition of BrCH2CN to a selection of styrenes. The formation of these turbocharged catalysts in situ during electrosynthesis offers a new approach to the Cu-catalyzed organic reaction methodology

Enzyme Electrode Biosensors for <i>N</i>‑Hydroxylated Prodrugs Incorporating the Mitochondrial Amidoxime Reducing Component

Human mitochondrial amidoxime reducing component 1 and 2 (mARC1 and mARC2) were immobilised on glassy carbon electrodes using the crosslinker glutaraldehyde. Voltammetry was performed in the presence of the artificial electron transfer mediator methyl viologen, whose redox potential lies negative of the enzymes’ MoVI/V and MoV/IV redox potentials which were determined from optical spectroelectrochemical and EPR measurements. Apparent Michaelis constants obtained from catalytic limiting currents at various substrate concentrations were comparable to those previously reported in the literature from enzymatic assays. Kinetic parameters for benzamidoxime reduction were determined from cyclic voltammograms simulated using Digisim. pH dependence and stability of the enzyme electrode with time were also determined from limiting catalytic currents in saturating concentrations of benzamidoxime. The same electrode remained active after at least 9 days. Fabrication of this versatile and cost-effective biosensor is effective in screening new pharmaceutically important substrates and mARC inhibitors

Insights into the Electronic Structure of Cu^II Bound to an Imidazole Analogue of Westiellamide

Three synthetic analogues of westiallamide, H3Lwa, have previously been synthesized (H3L1–3) that have a common backbone (derived from l-valine) with H3Lwa but differ in their heterocyclic rings (imidazole, oxazole, thiazole, and oxazoline). Herein we explore in detail through high-resolution pulsed electron paramagnetic resonance (EPR) and magnetic circular dichroism (MCD) spectroscopy in conjunction with density functional theory (DFT) the geometric and electronic structures of the mono- and dinuclear CuII complexes of these cyclic pseudo hexapeptides. Orientation-selective hyperfine sublevel correlation, electron nuclear double resonance, and three-pulse electron spin echo envelope modulation spectroscopy of [CuII(H2L1)­(MeOH)2]+ reveal delocalization of the unpaired electron spin onto the ligating and distal nitrogens of the coordinated heterocyclic rings and that they are magnetically inequivalent. DFT calculations confirm this and show similar spin densities on the distal heteroatoms in the heterocyclic rings coordinated to the CuII ion in the other cyclic pseudo hexapeptide [CuII(H2L2,3,wa)­(MeOH)2]+ complexes. The magnetic inequivalencies in [CuII(H2L1)­(MeOH)2]+ arise from different orientations of the heterocyclic rings coordinated to the CuII ion, and the delocalization of the unpaired electron onto the distal heteroatoms within these N-methylimidazole rings depends upon their location with respect to the CuII dx2–y2 orbital. A systematic study of DFT functionals and basis sets was undertaken to examine the ability to reproduce the experimentally determined spin Hamiltonian parameters. Inclusion of spin–orbit coupling (SOC) using MAG-ReSpect or ORCA with a BHLYP/IGLO-II Wachters setup with SOC corrections and ∼38% Hartree–Fock exchange gave the best predictions of the g and A(63Cu) matrices. DFT calculations of the 14N hyperfine and quadrupole parameters for the distal nitrogens of the coordinated heterocyclic rings in [CuII(H2L1)­(MeOH)2]+ with the B1LYP functional and the SVP basis set were in excellent agreement with the experimental data, though other choices of functional and basis set also provided reasonable values. MCD, EPR, mass spectrometry, and DFT showed that preparation of the dinuclear CuII complex in a 1:1 MeOH/glycerol mixture (necessary for MCD) resulted in the exchange of the bridging methoxide ligand for glycerol with a corresponding decrease in the magnitude of the exchange coupling

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

The di-2-pyridylketone thiosemicarbazones demonstrated marked anticancer efficacy, prompting progression of DpC to clinical trials. However, DpC induced deleterious oxy-myoglobin oxidation, stifling development. To address this, novel substituted phenyl thiosemicarbazone (PPP4pT) analogues and their Fe­(III), Cu­(II), and Zn­(II) complexes were prepared. The PPP4pT analogues demonstrated potent antiproliferative activity (IC50: 0.009–0.066 μM), with the 1:1 Cu:L complexes showing the greatest efficacy. Substitutions leading to decreased redox potential of the PPP4pT:Cu­(II) complexes were associated with higher antiproliferative activity, while increasing potential correlated with increased redox activity. Surprisingly, there was no correlation between redox activity and antiproliferative efficacy. The PPP4pT:Fe­(III) complexes attenuated oxy-myoglobin oxidation significantly more than the clinically trialed thiosemicarbazones, Triapine, COTI-2, and DpC, or earlier thiosemicarbazone series. Incorporation of phenyl- and styryl-substituents led to steric blockade, preventing approach of the PPP4pT:Fe­(III) complexes to the heme plane and its oxidation. The 1:1 Cu­(II):PPP4pT complexes were inert to transmetalation and did not induce oxy-myoglobin oxidation