Impact of organotin compounds on the growth of epidermoid Lewis carcinoma

Introduction: Search for new compounds with a broad antitumor and antimetastatic potency due to multiple targeting remains important in medicinal chemistry, pharmacology and oncology. We report the efficacy of hybrid organotin agents bis-(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (Ме3) and (3,5-di-tert-butyl-4-hydroxyphenylthiolate) triphenyltin (Ме5). Materials and methods: The compounds were administered to mice bearing the spontaneously metastatic epidermoid Lewis lung carcinoma (LLC). The efficacy of the treatment was evaluated by mean life span, percentage of tumor growth inhibition, number of lung metastases, frequency of metastasis, tumor weight 21 days after tumor cell inoculation, and a degree of lung damage according to the method of D. Tarin and J.E. Price. Results and discussion: For new organotin compounds containing an antioxidant protective fragment of 2,6-di-tert-butylphenol, moderate antitumor and pronounced antimetastatic effects were revealed in the Lewis model of epidermoid lung carcinoma; more active for Me5. Some features of the development of the process of metastasis were recorded with the introduction of various doses of hybrid organotin compounds. Conclusion: Substances Ме3 and Ме5 possess specific activity on the model under investigation, which allows one to suggest these organotins as promising series of antitumor and antimetastatic agents with multiple targeting mode of action.

Catalysts in the Direct Synthesis of Organotin Compounds. III. Reactions of Carbofunctional Organohalogenides with Metallic Tin

This is the third concluding part of a series of reviews devoted to the direct synthesis of organotin compounds. This review considers conditions and results of the interaction between metallic tin and carbofunctional organohalogenides. Efficiency of the catalysts application and advantages of the direct synthesis for the production of carbofunctional organotin compounds are analyzed.

Study of acute oral toxicity of organotin compounds containing a 2,6-di-tert-butylphenol fragment

The aim of the study was to evaluate the safety of the use of organotin compounds containing a fragment of 2,6-di-tert-butylphenol as pharmaceutical substances when administered intragastrically to Wistar outbred rats (females). Material and methods. The objects of the study were three organotin compounds: ((3,5-di-tertbutyl-4-hydroxyphenylthiolate) triphenyltin (Me-5), (3,5-di-tert-butyl-4-hydroxyphenylthiolate)trimethyltin (Me-4), bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (Me-3). Acute toxicity study were performed on 106 Wistar rats (female) weighing 190-210 g by "fixed dose" and "up and down" methods according to the OECD protocols. Results. According to the harmonized system of hazard classification and labeling of chemical products (GHS) the studied organotin compounds should be assigned to the following toxicity classes: Me-5 — IV, Me-3 — V, Me-4 — II. Average lethal dose in intragastric administration for Me-5 is LD50 = 955.0 ± 58.3 mg/kg, the value of LD50 for Me-3 is conventionally assumed to be much more than 2000 mg/kg, for Me-4 is in the range of 5 to 50 mg/kg. Discussion. The modification of tin-organic molecules in the course of directed synthesis opens broad prospects for the creation of a new class of anticancer drugs. In the course of the experimental study, the regularities of the "structure-toxicity" relationship of organic tin derivatives were revealed: the introduction of the 2,6-di-tert-butylphenol group significantly reduces toxicity compared to the corresponding initial substances; methyl derivatives are more toxic than their phenyl analogues. Compounds of GHS toxicity classes IV and V can be considered as leading candidates for promising preclinical studies in the field of experimental oncology. Conclusion. Substances of Me-3 and Me-5, which have the highest safety for intragastric use, were recommended for further study as antitumor drug agents.

Hybrid organotin compounds — modulators of apoptotic processes in the liver when administered once and repeatedly to Wistar rats

Introduction. The aim of the study was to evaluate the effect of hybrid organotin compounds bis(3,5–di– tert–butyl–4–hydroxyphenylthiolate) dimethylol (Me3) and ((3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenylolol (Me5) on the level of markers of oxidative stress and apoptotic processes in the mitochondria during acute and subchronic intragastric administration to Wistar rats (females) in the maximum tolerated dose. Materials and methods. The objects of study were hybrid organotin compounds, the administration was carried out at the maximum tolerated dose of 2000 mg/kg (Me3) and 750 mg/kg (Me5) with a single and multiple intragastric administration. The study was conducted on 60 Wistar rats (females) weighing 190-210g. The concentration of cytochrome C (ng / g protein), caspase-9(ng / g protein), 8-hydroxy-2' — deoxyguanosine (8-OHdG) (ng/g protein), malondialdehyde (MDA) (nM / g protein)was determined in mitochondrial liver samples using test systems by enzyme immunoassay; by the biochemical method-the amount of protein (mg / ml) — by the biuretic method. Results. Me3 in both series of the experiment showed itself as a more pronounced antioxidant than Me5, which did not show its antioxidant properties. In group I animals, there were no statistically significant differences in the level of MDA and Cit C in relation to the control group, no mitDNA damage was detected, but K9 activity increased by 17%. With the introduction of Me5, the value of the MDA indicator increased by 55.5%, 8 — OHdG by 12.4% and Cit C by 66.2%. In group IV, the amount of MDA as the final product of lipid peroxidation (POL) increased by 13.6%, in group V by 22.5%. With the introduction of Me3, the level of Cit C was reduced by 23.5%, with the introduction of Me5, on the contrary, it was slightly increased. K9 activity was reduced in both experimental groups, by 9.6% and 17.3%, respectively. Discussion. Hybrid OOS containing a fragment of 2,6-di-tert-butylphenol have a dual structure. The tin-containing component is prooxidant, and the radical of the spatially hindered phenol, on the contrary, is antioxidant. It is the different ratio of the described fragments in the molecules of the substances under study, in our opinion, that led to the appearance of different degrees of influence on the metabolism of mitochondria. Conclusion. Both substances that modulate changes in oxidative stress and the activity of apoptotic processes are recommended for further research as antitumor medicinal agents.

Chemistry of Some Organotin Compounds

Organotin compounds (OTCs) are characterized as having at minimum one covalent bond between carbon and tin atoms, and are usually denoted by the formula RnSnX4-n (n =1-3, R =aryl or alkyl, X =halogen ion or a carboxylate, etc.). There are several methods to synthesis organotin compounds, they are Grignard and Kocheshkov reactions, Wurtz reaction and alkylation method. The tin has two stable state,(II) and (IV). Sn(II) forms pyramidal sp3complexes as well as trigonal bipyramidal sp3d complexes, whereas Sn(IV) forms trigonal bipyramidal sp3d complexes or octahedral sp3d2complexes.