Organotin compound as an inhibitor of nitric oxide formation

The effect of antitumor and antimetastatic agent, triphenyltin (3,5-di- tert -butyl-4-hydroxyphenyl)thiolate (Me-5), on the in vitro activity of inducible nitric oxide synthase (iNOS) as a relevant biological target was studied. The compound Me-5 (the half-maximal inhibitory concentration IC 50 = 0.47 µmol L −1 ) induced a significant inhibition of NO formation by macrophages, exceeding that of dexamethasone used as the reference compound (IC 50 = 1.55 µmol L −1 ). Estimation of the morphology of macrophages after incubation with Me-5 in 10 µmol L −1 concentration revealed signs of the pronounced cytotoxicity: destruction of cell membranes, reduction of cell volume, chromatin condensation, and nuclear shrinkage. It was found that the organotin compound substantially inhibits the anti-inflammatory response and viability of macrophages, especially the functions of lysosomes. Molecular docking of Me-5 into the iNOS structure was carried out. According to calculations, the molecule is located at the entrance of the active site cavity, above the plane of the heme moiety, and hinders the substrate penetration into the active site, which may attest to a plausible mechanism of antitumor and antimetastatic action of Me-5.