Add time:07/25/2019         Source:sciencedirect.com

A series of cytotoxic organotin compounds 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), synthesized recently, have been used to study the possible mechanisms of their cytotoxicity. With this aim we have investigated the influence of organotin compounds 1–7 as well as their precursor R2SnCl2 (8) on tubulin assembly in microtubules. Compounds 1, 6–8 reveal the statistically significant inhibition of tubulin polymerization without notable disturbances of microtubules structure. Docking simulations revealed the possibility of organotin compounds to bind in the paclitaxel or vinblastine sites on the tubulin surface, but the mechanism of action of the compounds could not be explained based solely on these data. The influence on mitochondrial potential and induction of mitochondrial permeability transition also have been studied. Organotin compound 7 depolarises the mitochondria and induces the mitochondrial permeability transition. These properties may be the main reason of its cytotoxicity. Since the organotins possess the protective 2,6-di-tert-butylphenol groups the antioxidant potential of these compounds as inhibitors of mitochondrial lipid peroxidation was studied. All compounds under investigation effectively inhibit the Fe3+-induced mitochondrial lipid peroxidation. The comparative study of structure-activity relationship in the lipid peroxidation inhibition was performed. The influence of the organic groups nature, the number of hindered phenol fragments in organotins on their toxic effect is discussed. The introduction of hindered phenol groups decreases the cytotoxicity of compounds. This result opens up the possibility of designing novel anticancer drugs that might possess lower undesirable toxicity against normal cells.

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