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.

Synthesis, antiradical activity and in vitro cytotoxicity of novel organotin complexes based on 2,6-di-tert-butyl-4-mercaptophenol.

A series of organotin complexes with Sn-S bonds of formulae Me2Sn(SR)2 (1); Et2Sn(SR)2 (2); (n-Bu)2Sn(SR)2 (3); Ph2Sn(SR)2 (4); R2Sn(SR)2 (5); Me3SnSR (6); Ph3SnSR (7) (R = 3,5-di-tert-butyl-4-hydroxyphenyl) were synthesized and characterized by elemental analysis, (1)H, (13)C NMR, and IR. The crystal structures of compounds 1, 4, 5, and 7 were determined by X-ray diffraction analysis. The tetrahedral geometry around the Sn center in the monocrystals of 1, 4, 5, and 7 was confirmed by X-ray crystallography. The high radical scavenging activity of the complexes was confirmed spectrophotometrically in a DPPH-test. The binding affinity of 1-7 and the starting R2SnCl2 (8) towards tubulin through their interaction with SH groups of proteins was studied. It was found that the hindered organotin complexes could interact with the colchicine site of tubulin, which makes them promising antimitotic drugs. Compounds 1-8 were tested for their in vitro cytotoxicity against human breast (MCF-7) and human cervix (HeLa) adenocarcinoma cells. Complexes 1-8 were also tested against normal human fetal lung fibroblast cells (MRC-5). Complexes 2-4 and 8 exhibit significantly lower cytostatic activity against the normal MRC-5 cell line compared to the tumor cell lines MCF-7 and HeLa used. A high activity against both cell lines 250 nM (MCF-7) and 160 nM (HeLa) was determined for the triphenyltin complex 7 while the introduction of hindered phenol groups decreases the cytotoxicity of the complexes against normal cells.

[The establishment of the maximum permissible concentration of orlok in the air of a work area when used in agriculture]. / Obosnovanie predel'no dopustimoi kontsentratsii orloka v vozdukhe rabochei zony pri primenenii v sel'skom khoziaistve.

Inhaled Orlok causes changes in the CNS, blood morphology, renal function. The threshold concentration of Orlok is 0.17 mg/m3, its subthreshold concentration is 0.023 mg/m3, MAC in the workplace air is 0.05 mg/m3.