A Study of Catalytic Oxidation of a Library of C2 to C4 Alcohols in the Presence of Nanogold.

The classical stoichiometric oxidation of alcohols is an important tool in contemporary organic chemistry. However, it still requires huge modifications in order to comply with the principles of green chemistry. The use of toxic chemicals, hazardous organic solvents, and the large amounts of toxic wastes that result from the reactions are a few examples of the problems that must be solved. Nanogold alone or conjugated with palladium were supported on different carriers (SiO2, C) and investigated in order to evaluate their catalytic potential for environmentally friendly alcohol oxidation under solvent-free and base-free conditions in the presence H2O2 as a clean oxidant. We tested different levels of Au loading (0.1⁻1.2% wt.) and different active catalytic site forms (monometallic Au or bimetallic Au⁻Pd sites). This provided new insights on how the structure of the Au-dispersions affected their catalytic performance. Importantly, the examination of the catalytic performance of the resulting catalysts was oriented toward a broad scope of alcohols, including those that are the most resistant to oxidation-the primary aliphatic alcohols. Surprisingly, the studies proved that Au/SiO2 at a level of Au loading as low as 0.1% wt. appeared to be efficient and prospective catalytic system for the green oxidation of alcohol. Most importantly, the results revealed that 0.1% Au/SiO2 might be the catalyst of choice with a wide scope of utility in the green oxidation of various structurally different alcohols as well as the non-activated aliphatic ones.

Piperazinyl fragment improves anticancer activity of Triapine.

A new class of TSCs containing piperazine (piperazinylogs) of Triapine, was designed to fulfill the di-substitution pattern at the TSCs N4 position, which is a crucial prerequisite for the high activity of the previously obtained TSC compounds-DpC and Dp44mT. We tested the important physicochemical characteristics of the novel compounds L1-L12. The studied ligands are neutral at physiological pH, which allows them to permeate cell membranes and bind cellular Fe pools more readily than less lipid-soluble ligands, e.g. DFO. The selectivity and anti-cancer activity of the novel TSCs were examined in a variety of cancer cell types. In general, the novel compounds demonstrated the greatest promise as anti-cancer agents with both a potent and selective anti-proliferative activity. We investigated the mechanism of action more deeply, and revealed that studied compounds inhibit the cell cycle (G1/S phase). Additionally we detected apoptosis, which is dependent on cell line's specific genetic profile. Accordingly, structure-activity relationship studies suggest that the combination of the piperazine ring with Triapine allows potent and selective anticancer chelators that warrant further in vivo examination to be identified. Significantly, this study proved the importance of the di-substitution pattern of the amine N4 function.

Iron chelating strategies in systemic metal overload, neurodegeneration and cancer.

Iron is a trace element required for normal performance of cellular processes. Because both the deficiency and excess of this metal are dangerous, its absorption, distribution and accumulation must be tightly regulated. Disturbances of iron homeostasis and an increase in its level may lead to overload and neurodegenerative diseases. Phlebotomy was for a long time the only way of removing excess iron. But since there are many possible disadvantages of this method, chelation therapy seems to be a logical approach to remove toxic levels of iron. In clinical use, there are three drugs: desferrioxamine, deferiprone and deferasirox. FBS0701, a novel oral iron chelator, is under clinical trials with very promising results. Developing novel iron-binding chelators is an urgent matter, not only for systemic iron overload, but also for neurodegenerative disorders, such as Parkinson's disease. Deferiprone is also used in clinical trials in Parkinson's disease. In neurodegenerative disorders the main goal is not only to remove iron from brain tissues, but also its redistribution in system. Few chelators are tested for their potential use in neurodegeneration, such as nonhalogeneted derivatives of clioquinol. Such compounds gave promising results in animal models of neurodegenerative diseases. Drugs of possible use in neurodegeneration must meet certain criteria. Their development includes the improvement in blood brain barrier permeability, low toxicity and the ability to prevent lipid peroxidation. One of the compounds satisfying these requirements is VK28. In rat models it was able to protect neurons in very low doses without significantly changing the iron level in liver or serum. Also iron chelators able to regulate activity of monoamine oxidase were tested. Polyphenols and flavonoids are able to prevent lipid peroxidation and demonstrate neuroprotective activity. While cancer does not involve true iron overload, neoplastic cells have a higher iron requirement and are especially prone to its depletion. It was shown, that desferrioxamine and deferasirox are antiproliferative agents active in several types of cancer. Very potent compounds with possible use as anticancer drugs are thiosemicarbazones. They are able to inhibit ribonucleotide reductase, an enzyme involved in DNA synthesis. Because the relationship between the development of overload / neurodegenerative disorders, or cancer, and iron are very complex, comprehension of the mechanisms involved in the regulation of iron homeostasis is a crucial factor in the development of new pharmacological strategies based on iron chelation. In view of various factors closely involved in pathogenesis of such diseases, designing multifunctional metal-chelators seems to be the most promising approach, but it requires a lot of effort. In this perspective, the review summarizes systemic iron homeostasis, and in brain and cancer cells, iron dysregulation in neurodegenerative disease and possible chelation strategies in the treatment of metal systemic overload, neurodegeneration and cancer.

A dinuclear zinc(II) complex of a new unsymmetric ligand with an N(5)O(2) donor set: a structural and functional model for the active site of zinc phosphoesterases.

The dinuclear complex [Zn(2)(DPCPMP)(pivalate)](ClO4), where DPCPMP is the new unsymmetrical ligand [2-(N-(3-((bis((pyridin-2-yl)methyl)amino)methyl)-2-hydroxy-5-methylbenzyl)-N-((pyridin-2-yl)methyl)amino)acetic acid], has been synthesized and characterized. The complex is a functional model for zinc phosphoesterases with dinuclear active sites. The hydrolytic efficacy of the complex has been investigated using bis-(2,4-dinitrophenyl)phosphate (BDNPP), a DNA analog, as substrate. Speciation studies using potentiometric titrations have been performed for both the ligand and the corresponding dizinc complex to elucidate the formation of the active hydrolysis catalyst; they reveals that the dinuclear zinc(II) complexes, [Zn(2)(DPCPMP)](2+) and [Zn(2)(DPCPMP)(OH)](+) predominate the solution above pH4. The relatively high pK(a) of 8.38 for water deprotonation suggests that a terminal hydroxide complex is formed. Kinetic investigations of BDNPP hydrolysis over the pH range 5.5-11.0 and with varying metal to ligand ratio (metal salt:ligand=0.5:1 to 3:1) have been performed. Variable temperature studies gave the activation parameters ΔH(‡)=95.6kJmol(-1), ΔS(‡)=-44.8Jmol(-1)K(-1), and ΔG(‡)=108.0 kJmol(-1). The cumulative results indicate the hydroxido-bridged dinuclear Zn(II) complex [Zn(2)(DPCPMP)(µ-OH)](+) as the effective catalyst. The mechanism of hydrolysis has been probed by computational modeling using density functional theory (DFT). Calculations show that the reaction goes through one concerted step (S(N)2 type) in which the bridging hydroxide in the transition state becomes terminal and performs a nucleophilic attack on the BDNPP phosphorus; the leaving group dissociates simultaneously in an overall inner sphere type activation. The calculated free energy barrier is in good agreement with the experimentally determined activation parameters.