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The number of substituted pyridine pyridinophanes found in the literature is limited due to challenges associated with 12-membered macrocycle and modified pyridine synthesis. Most notably, the electrophilic character at the 4-position of pyridine in pyridinophanes presents a unique challenge for introducing electrophilic chemical groups. Likewise, of the few reported, most substituted pyridine pyridinophanes in the literature are limited to electron-donating functionalities. Herein, new synthetic strategies for four new macrocycles bearing the electron-withdrawing groups CN, Cl, NO(2), and CF(3) are introduced. Potentiometric titrations were used to determine the protonation constants of the new pyridinophanes. Further, the influence of such modifications on the chemical behavior is predicted by comparing the potentiometric results to previously reported systems. X-ray diffraction analysis of the 4-Cl substituted species and its Cu(II) complex are also described to demonstrate the metal binding nature of these ligands. DFT analysis is used to support the experimental findings through energy calculations and ESP maps. These new molecules serve as a foundation to access a range of new pyridinophane small molecules and applications in future work.

Owing to the increasing importance of manganese(II) complexes in the field of magnetic resonance imaging (MRI), large efforts have been devoted to find an appropriate ligand for Mn(II) ion encapsulation by providing balance between the seemingly contradictory requirements (i.e., thermodynamic stability and kinetic inertness vs low ligand denticity enabling water molecule(s) to be coordinated in its metal center). Among these ligands, a large number of pyridine or pyridol based open-chain and macrocyclic chelators have been investigated so far. As a next step in the development of these chelators, 15-pyN(3)O(2)Ph and its transition metal complexes were synthesized and characterized using established methods. The 15-pyN(3)O(2)Ph ligand incorporates both pyridine and ortho-phenylene units to decrease ligand flexibility. The thermodynamic properties, protonation and stability constants, were determined using pH-potentiometry; the solid-state structures of two protonation states of the free ligand and its manganese complex were obtained by single crystal X-ray diffractometry. The results show a seven-coordinate metal center with two water molecules in the first coordination sphere. The longitudinal relaxivity of [Mn(15-pyN(3)O(2)Ph)](2+) was found to be 5.16 mM(−1) s(−1) at 0.49 T (298 K). Furthermore, the [Formula: see text] value of 11.72 mM(−1) s(−1) (0.49 T), which is doubled at 1.41 T field, suggests that design of this Mn(II) complex does achieve some characteristics required for contrast imaging. In addition,(17)O NMR measurements were performed in order to access the microscopic parameters governing this key feature (e.g., water exchange rate). Finally, manganese complexes of ligands with analogous polyaza macrocyclic scaffold have been investigated as low molecular weight Mn(CAT) mimics. Here, we report the H(2)O(2) disproportionation study of [Mn(15-pyN(3)O(2)Ph)](2+) to demonstrate the versatility of this ligand scaffold as well.

The use of tetra-aza pyridinophanes is of increasing interest in the fields of bioinorganic modeling, catalysis, and imaging. However, a full study of how modifications to the pyridyl moiety affect the characteristics of the daughter metal complexes, has not been explored. In this study, six tetra-aza macrocyclic ligands were metalated with Fe(iii) and were characterized for the first time. The pyridyl functional groups studied include: 4-hydroxyl (L1), 4-H (L2), 4-chloro (L3), 4-trifluoromethyl (L4), 4-nitrile (L5), and 4-nitro (L6) modified pyridyl on a pyclen base structure. The resulting iron complexes were characterized by X-ray diffraction analysis, cyclic voltammetry, and metal-binding affinities (log β) were determined. Analysis of these results indicate that such functionalizations introduce a handle by which electrochemical properties and thermodynamic stability of daughter complexes with transition metal ions can be tuned, which in turn, could potentially impact the reactivity of these complexes in future studies.

The catalase family of enzymes, which include a variety with a binuclear manganese active site, mitigate the risk from reactive oxygen species by facilitating the disproportionation of hydrogen peroxide into molecular oxygen and water. In this work, hydrogen peroxide disproportionation using complexes formed between manganese and cyclen or pyclen were investigated due to the spectroscopic similarities with the native MnCAT enzyme. Potentiometric titrations were used to construct speciation diagrams that identify the manganese complex compositions at different pH values. Each complex behaves as a functional mimic of catalase enzymes. UV-visible spectroscopic investigations of the H(2)O(2) decomposition reaction yielded information about the structure of the initial catalyst and intermediates that include monomeric and dimeric species. The results indicate that rigidity imparted by the pyridine ring of pyclen is a key factor in increased TON and TOF values measured compared to cyclen.

Alzheimer’s and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12-membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H(2)O(2))-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H(2)O(2) cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.

In this work, we utilize a bottom-up approach to synthesize nitrogen self-doped graphene quantum dots (NGQDs) from a single glucosamine precursor via an eco-friendly microwave-assisted hydrothermal method. Structural and optical properties of as-produced NGQDs are further modified using controlled ozone treatment. Ozone-treated NGQDs (Oz-NGQDs) are reduced in size to 5.5 nm with clear changes in the lattice structure and ID/IG Raman ratios due to the introduction/alteration of oxygen-containing functional groups detected by Fourier-transform infrared (FTIR) spectrometer and further verified by energy dispersive X-ray spectroscopy (EDX) showing increased atomic/weight percentage of oxygen atoms. Along with structural modifications, GQDs experience decrease in ultraviolet–visible (UV–vis) absorption coupled with progressive enhancement of visible (up to 16 min treatment) and near-infrared (NIR) (up to 45 min treatment) fluorescence. This allows fine-tuning optical properties of NGQDs for solar cell applications yielding controlled emission increase, while controlled emission quenching was achieved by either blue laser or thermal treatment. Optimized Oz-NGQDs were further used to form a photoactive layer of solar cells with a maximum efficiency of 2.64% providing a 6-fold enhancement over untreated NGQD devices and a 3-fold increase in fill factor/current density. This study suggests simple routes to alter and optimize optical properties of scalably produced NGQDs to boost the photovoltaic performance of solar cells.

International audience; We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms at either positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability [log KMnL = 17.09(2)] than the 3,6-PC2A analogue [log KMnL = 15.53(1); 0.15 M NaCl]. Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM–1 s–1 for the complexes with 3,6-PC2A and 3,9-PC2A, respectively, at 25 °C and 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex298) are 140 × 106 and 126 × 106 s–1 for [Mn(3,6-PC2A)(H2O)] and [Mn(3,9-PC2A)(H2O)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with half-lives of 63 and 21 h, respectively, at pH = 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)(H2O)]2– (H4EDTA = ethylenediaminetetraacetic acid) and [Mn(PhDTA)(H2O)]2– (H4PhDTA = phenylenediamine-N,N,N′,N′-tetraacetic acid), indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/p-nitro blue tetrazolium chloride assay at pH = 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable of assisting decomposition of the superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by 1 order of magnitude than that of 3,6-PC2A.

We report the Mn(II) complexes with two pyclen-based ligands (pyclen = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene) functionalized with acetate pendant arms either at positions 3,6 (3,6-PC2A) or 3,9 (3,9-PC2A) of the macrocyclic fragment. The 3,6-PC2A ligand was synthesized in five steps from pyclen-oxalate by protecting one of the secondary amine groups of pyclen using Alloc protecting chemistry. The complex with 3,9-PC2A is characterized by a higher thermodynamic stability (logKMnL = 17.09(2) than the 3,6-PC2A analogue (logKMnL = 15.53(1), 0.15 M NaCl). Both complexes contain a water molecule coordinated to the metal ion, which results in relatively high 1H relaxivities (r1p = 2.72 and 2.91 mM-1 s -1 for the complexes with 3,6- and 3,9-PC2A, respectively, 25 ºC, 0.49 T). The coordinated water molecule displays fast exchange kinetics with the bulk in both cases; the rates (kex 298) are 140106 and 126106 s -1 for [Mn(3,6-PC2A)] and [Mn(3,9- PC2A)], respectively. The two complexes were found to be remarkably inert with respect to their dissociation, with halflives of 63 and 21 h, respectively, at pH 7.4 in the presence of excess Cu(II). The r1p values recorded in blood serum remain constant at least over a period of 120 h. Cyclic voltammetry experiments show irreversible oxidation features shifted to higher potentials with respect to [Mn(EDTA)]2- and [Mn(PhDTA)]2- , indicating that the PC2A complexes reported here have a lower tendency to stabilize Mn(III). The superoxide dismutase activity of the Mn(II) complexes was tested using the xanthine/xanthine oxidase/NBT assay at pH 7.8. The Mn(II) complexes of 3,6-PC2A and 3,9-PC2A are capable to assist the decomposition of superoxide anion radical. The kinetic rate constant of the complex of 3,9-PC2A is smaller by one order of magnitude than that of 3,6-PC2A.

The pyridinophane molecule L2 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) has shown promise as a therapuetic for neurodegenerative diseases involving oxidative stress and metal ion misregulation. Protonation and metal binding stability constants with Mg(2+), Ca(2+), Cu(2+), and Zn(2+) ions were determined to further explore the therapeutic and pharmacological potential of this water soluble small molecule. These studies show that incorporation of an –OH group in position 4 of the pyridine ring decreases the pI values compared to cyclen and L1 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-triene). Furthermore, this approach tunes the basicity of the tetra-aza macrocyclic ligand through the enhanced resonance stabilization of the –OH in position 4 and rigidity of the pyridine ring such that L2 has increased basicity compared to previously reported tetra-aza macrocycles. A metal binding preference for Cu(2+), a redox cycling agent known to produce oxidative stress, indicates that this would be the in vivo metal target of L2. However, the binding constant of L2 with Cu(2+) is moderated compared to cyclen due to the rigidity of the ligand and shows how ligand design can be used to tune metal selectivity. An IC(50)=298.0 µM in HT-22 neuronal cells was observed. Low metabolic liability was determined in both Phase I and II in vitro models. Throughout these studies other metal binding systems were used for comparison and as appropriate controls. The reactivity reported to date and pharmacological features described herein warrant further studies in vivo and the pursuit of L2 congeners using the knowledge that pyridine substitution in a pyridinophane can be used to tune the structure of the ligand and retain the positive therapeutic outcomes.

Growth of the library of tetraaza macrocyclic pyridinophane ligands is a result of the potential to treat neurodegenerative diseases by binding unregulated redox active metal-ions, scavenging radicals, and reducing oxidative stress. As part of this work, the copper complex of (OH)PyN(3)Cu (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) was previously identified as a discrete molecule in the solid state when isolated at lower pH values. However, here we report that (OH)PyN(3)Cu forms a helical structure upon crystallization around pH 6.5. Several properties of the ligand and complex were evaluated to understand the driving forces that led to the concatenation and formation of this solid-state helix. DFT studies along with a comparison of keto/enol tautomerization stability and bond lengths were used to determine the keto-character of the C=O within each subunit. This pH dependent keto-enol tautomerization is responsible for the solid state intermolecular C=O···Cu bonds observed in this metallohelix (Cu1(H)) when produced around pH 6.5. Perchlorate templating that occurs through hydrogen bonding between perchlorate counter ions and each Cu1(H) unit is the primary driving factor for the twist that leads to the helix structure. Cu1(H) does not exhibit the typical factors that stabilize the formation of helices, such as intra-strand hydrogen bonding or π-stacking. The helix structure further highlights the diversity of inorganic metallohelices and demonstrates the importance of tautomerization and pH that occurs with the pyridinophane ligand used in this study. To our knowledge and although these phenomenon have been observed individually, this is the first example of a pH dependent keto-enol tautomerization in an azamacrocycle being the driving force for the formation of a metallohelix solid state structure and is a particularly unique observation for pyridinophane complexes.

In line with our research to find inert Mn(II) complexes as contrast agents for magnetic resonance imaging, we have studied the aromatic-ring rigidified EDTA-analogue o-phenylenediamine-N,N,N′,N′-tetraacetic acid (PhDTA). The protonation constants (KHi) of PhDTA and stability constants of complexes formed between this open-chain ligand and several different biogenic metal ions (Ca2+, Mg2+, Zn2+, Cu2+, Mn2+) have been determined in 0.15 M NaCl at 25 °C and compared with the values reported in the literature previously. The protonation constants are lower than those of the corresponding cis- and trans-CDTA complexes, which might be attributed to the electron withdrawing effect of the phenylene group. The lower total basicity of the ligand leads to lower stability constants for all the examined metal complexes. On the contrary, we have found that the conditional stability constants of [Mn(PhDTA)]2− and [Mn(trans-CDTA)]2− are approximately the same, as both complexes are completely formed at pH 5 and their pM values are also comparable. The relaxivity of [Mn(PhDTA)]2− is nearly identical (r1 = 3.72 mM−1 s−1) to that determined previously for the [Mn(trans-CDTA)]2− complex (r1 = 3.62 mM−1 s−1), and its pH-dependence confirms the equilibrium model used for the fitting of the titration data. The results of the kinetic studies of the metal exchange reactions reveal that the [Mn(PhDTA)]2− complex possesses a slightly better dissociation kinetics profile than that of [Mn(trans-CDTA)]2−, which has been tested in vivo recently (including human injections). The half-life of the dissociation of the complex near physiological pH at 25 °C is 19 hours. By using the rate constant calculated for the dissociation (pH = 7.4, cCu2+ = 10 μM) and the half-life of excretion (1.6 hour), the ratio of the dissociated complex is estimated to represent 8% of the injected dose. DFT studies reveal that the metal coordination environment of [Mn(PhDTA)]2− is very similar to that of [Mn(EDTA)]2−, both containing an inner-sphere water molecule. Cyclic voltammetry studies indicate that [Mn(PhDTA)]2− is slightly more resistant towards oxidation to the Mn3+ complex than the EDTA analogue.

Correction for ‘Functionalized pyridine in pyclen-based iron(iii) complexes: evaluation of fundamental properties’ by Magy A. Mekhail et al., RSC Adv., 2020, 10, 31165–31170. DOI: 10.1039/d0ra05756h.

Metal-ion misregulation and oxidative stress continue to be components of the continually evolving hypothesis describing the molecular origins of Alzheimer's disease. Therefore, these features are viable targets for synthetic chemists to explore through hybridizations of metal-binding ligands and antioxidant units. To date, the metal-binding unit in potential therapeutic small molecules has largely been inspired by clioquinol with the exception of a handful of heterocyclic small molecules and open-chain systems. Heterocyclic small molecules such as cyclen (1,4,7,10-tetraazacyclododecane) have the advantage of straightforward N-based modifications, allowing the addition of functional groups. In this work, we report the synthesis of a triazine bridged system containing two cyclen metal-binding units and an antioxidant coumarin appendage inspired by nature. This new potential therapeutic molecule shows the ability to bind copper in a unique manner compared to other chelates proposed to treat Alzheimer's disease. DPPH and TEAC assays exploring the activity of N-(2-((4,6-di(1,4,7,10-tetraazacyclododecan-1-yl)-1,3,5-triazin-2-yl)amino)ethyl)-2-oxo-2H-chromene-3-carboxamide (molecule 1) show that the molecule is antioxidant. Cellular studies of molecule 1 indicate a low toxicity (EC