Rapid and low overpotential oxidation of water to dioxygen remains a key hurdle for storage of solar energy. Here, we address this issue by demonstrating that deprotonation of 2-(2'-pyridyl)-imidazole (pimH)-ligated copper complexes promotes water oxidation at low overpotential and low catalyst loading. This improves upon other work on homogeneous copper-based water oxidation catalysts, which are highly active, but limited by high overpotentials. EPR and UV-vis spectroscopic evaluation of catalyst speciation shows that at pH ≥ 12 coordinated pimH is deprotonated and a bis(hydroxide) Cu active catalyst forms. Rapid electrochemical water oxidation (35 s, 0.85 V onset potential) was observed with 150 μM catalyst. These results demonstrate that catalytic water oxidation potentials can be shifted by hundreds of mV in homogeneous metal catalysts bearing an ionisable imidazole ligand.
The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for (19)F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient D at pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using (19)F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. (19)F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes.
An Fe corrole is shown to bind to the amyloid-beta peptide and limit reactive oxygen species generation and peptide aggregation of relevance to Alzheimer's disease.
Electron paramagnetic resonance spectroscopy (EPR) is an invaluable method for characterizing ligand environments and oxidation states of paramagnetic metal complexes. In this review we describe applications of this technique to understanding the often complicated mechanisms of metal-based anticancer compounds. EPR has been instrumental in unravelling this in many instances, providing insight into conformations upon dissolution, aqueous ligand exchange, pH effects, and redox processes. EPR studies have also characterized the pro-
Organometallic Ru(II)-cymene complexes
linked to ferrocene (Fc)
via nitrogen heterocycles have been synthesized and studied as cytotoxic
agents. These compounds are analogues of Ru(II)-arene piano-stool
anticancer complexes such as RAPTA-C. The Ru center was coordinated
by pyridine, imidazole, and piperidine with 0-, 1-, or 2-carbon bridges
to Fc to give six bimetallic, dinuclear compounds, and the properties
of these complexes were compared with their non-Fc-functionalized
parent compounds. Crystal structures for five of the compounds, their
Ru-cymene parent compounds, and an unusual trinuclear compound were
determined. Cyclic voltammetry was used to determine the formal MIII/II potentials of each metal center of the Ru-cymene-Fc
complexes, with distinct one-electron waves observed in each case.
The Fc-functionalized complexes were found to exhibit good cytotoxicity
against HT29 human colon adenocarcinoma cells, whereas the parent
compounds were inactive. Similarly, antibacterial activity from the
Ru-cymene-Fc compounds was observed against Bacillus
subtilis, but not from the unfunctionalized complexes.
In both cases, the IC50 values correlated quantitatively
with the Fc+/0 reduction potentials. This is consistent
with more facile oxidation to give ferrocenium, and subsequent generation
of toxic reactive oxygen species, leading to greater cytotoxicity.
The antioxidant properties of the complexes were quantified by a 2,2-diphenyl-1-picrylhydrazyl
(DPPH) radical scavenging assay. EC50 values indicate that
linking of the Ru and Fc centers promotes antioxidant activity.
The
3-dimensional (3D) structure of therapeutics and other bioactive
molecules is an important factor in determining the strength and selectivity
of their protein–ligand interactions. Previous efforts have
considered the strain introduced and tolerated through conformational
changes induced upon protein binding. Herein, we present an analysis
of 3-dimentionality for energy-minimized structures from the DrugBank
and ligands bound to proteins identified in the Protein Data Bank
(PDB). This analysis reveals that the majority of molecules found
in both the DrugBank and the PDB tend toward linearity and planarity,
with few molecules having highly 3D conformations. Decidedly 3D geometries
have been historically difficult to achieve, likely due to the synthetic
challenge of making 3D organic molecules, and other considerations,
such as adherence to the ‘rule-of-five’. This has resulted
in the dominance of planar and/or linear topologies of the molecules
described here. Strategies to address the generally flat nature of
these data sets are explored, including the use of 3D organic fragments
and inorganic scaffolds as a means of accessing privileged 3D space.
This work highlights the potential utility of libraries with greater
3D topological diversity so that the importance of molecular shape
to biological behavior can be more fully understood in drug discovery
campaigns.
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