The antioxidant 2,6-di-tert-butylphenol moiety attenuates the pro-oxidant properties of the auranofin analogue.

Metal-based drugs are gaining momentum as a rapidly developing area of medicinal inorganic chemistry. Among gold pharmaceuticals, auranofin is a well known antirheumatic drug. The efficacy of gold-organic complexes largely depends on their pro-oxidant properties since auranofin targets the redox enzyme thioredoxin reductase (TrxR). However, an uncontrollable oxygen burst may be harmful for healthy cells; therefore, the search for chemical modifications to attenuate oxidation-related general toxicity of gold containing anti-inflammatory drugs is justified. In this study, we demonstrate that the incorporation of a specific antioxidant phenol fragment can counterbalance the pro-oxidative potential of the Au containing complex molecule. The electrochemical studies of AuPPh3SR (1, R= 3,5-di-tert-butyl-4-hydroxyphenyl) and its precursors AuPPh3Cl (2) and RSH (3) showed that complex 1 and phenol 3 efficiently scavenged the radicals (as detected by cyclic voltammetry) whereas 2 had no effect. Compound 1 inhibited TrxR in vitro with IC50 0.57 ± 0.15 µM, a value one order of magnitude bigger than the potency reported for auranofin. Compound 1 (5 mg kg-1 daily gavage for 14 days) caused a decrease in ex vivo spontaneous and ascorbate-induced lipid peroxidation in the homogenates of rat lung, heart muscle, spleen, liver, kidneys, testicles and brain as assessed by the thiobarbituric acid reactive substances. Importantly, in animals fed with 1, no discernible general toxicity was registered suggesting that this compound is well tolerated. Our results provide evidence for an efficient synthetic route to obtain gold containing anti-inflammatory drug candidates with balanced pro/anti-oxidative properties.

[Regulation of nitrate metabolism through anion polycompartmentation in plant roots]. / Reguliatsiia metabolizma nitrata s uchastiem sistemy polikompartmentatsii aniona v korniakh rastenii.

A new concept illustrated by a corresponding mathematical model of nitrate metabolism regulation is proposed. The model is based on root nitrate compartmentation in several functional pools: storage, metabolic and a mobile pool which is intended for translocation to shoots. Data on nitrate uptake, compartmentation, reduction in intact roots and translocation to shoots were obtained on steady-state wheat seedlings grown at 25 and 12 degrees C in the root zone. The net uptake, influx/efflux ratio, mobile pool size and translocation changed depending on the medium temperature. The oscillations of the net uptake rate, nitrate tissue concentration were revealed and the effect of temperature on these changes was demonstrated. The scheme of regulation is based on the idea that net uptake through nitrate influx/efflux is under the control of the nitrate the mobile pool whose size was dependent on the nitrate translocation into shoots. The mathematical model is represented by a system of ordinary differential equations simplified according to the time hierarchy of reactions. It has a limit cycle at definite values of the parameters. The model postulates the mechanism of a positive feed-back regulation of the transfer of newly absorbed nitrate into translocated pool formed in the root cortex. Theoretical results are verified experimentally.