Aim. To identify the most suitable pathogenetic mechanisms for in-depth study of the antitumor and antimetastatic effects of tested hybrid organotin compounds using the immunohistochemical approach.Materials and Methods. Here, we tested bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate) dimethyltin (laboratory code Me-3), belonging to the class of hybrid organotin compounds, on 30 female C57Bl/6 mice using a universal model of transplantable tumors with spontaneous metastasis (B16 melanoma). 48 hours after tumor cell transplantation, we intraperitoneally administered Me-3 once daily to female C57Bl/6 mice for 10 days at a total dose (TD) of 375 mg/kg. For histological analysis, we used the primary tumor node of B16 melanoma. Immunophenotyping of B16 melanoma tissue samples was carried out using the polyclonal antibodies to transforming growth factor beta 1 (TGFβ-1), vascular endothelial growth factor A (VEGFA), Bcl2-associated X Protein (Bcl-2), cluster of differentiation 34 (CD34).Results. After the exposure to Me-3, we found a reduced immunohistochemical signal to TGF-β1 and Bcl-2 3 in the tumor tissue. Low doses of Me-3 have also impacted angiogenesis.Conclusion. Me-3 has a pro-apoptotic and anti-angiogenetic effects on B16 melanoma cells in C57Bl/6 mice.

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 IC50 = 0.47 µmol L−1) induced a significant inhibition of NO formation by macrophages, exceeding that of dexamethasone used as the reference compound (IC50 = 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.

New complexes I – IV of di- tert -butyltin with ligands based on heterocyclic thioamides (2-mercaptobenzoxazole, 2-mercaptobenzothiazole, 2-mercaptobenzimidazole) and 2,6-di- tert -butyl-4-mercaptophenol are synthesized and studied by X-ray diffraction (XRD). The XRD results for single crystals of I , II , and IV are presented (CIF files CCDC nos. 2251495, 2251493, and 2251494, respectively). Specific features of the synthesized crystal structures are discussed. Complexes I and II contain the expected Sn–C and Sn–S bonds and an additional coordination with the nitrogen atom in the heterocycles, which indicates the octahedral environment of the Sn(IV) atom (coordination number 6). The coordination polyhedron in complex IV can be described as a distorted tetrahedron (coordination number 4). The proposed compounds are studied as antiproliferative agents. Their antiproliferative activity is determined using the human cancer cell lines (PC3, MCF-7, НСT116, A549, and normal cells WI38). A dependence of the activity on the ligand structure is found. A comparative evaluation of the activity shows that the introduction of the antioxidant 2,6-di- tert -butyl-4-mercaptophenol fragment into complex IV substantially decreases the cytotoxicity.

Introduction. Organotin compounds are promising candidates for antitumor drugs. Identification of pathogenetic features of the general toxic effect of hybrid organotin compounds during the period of the greatest severity of the intoxication clinical picture will allow to estimate the risk of hepatotoxic and nephrotoxic complications with the administration of bis (3,5–di–tert–butyl–4–hydroxyphenylthiolate) dimethyltin (Me-3) and ((3,5–di–tert–butyl–4–hydroxyphenylthiolate) triphenyltin (M-e5) as chemotherapeutic agents.The aim of the study is to conduct a comparative analysis of morphological and biochemical changes with a single intragastric administration of hybrid organotin compounds Me–3 and Me-5 in the maximum tolerated dose (MTD) on the 7th day of the toxic process development.Material and Methods. Hybrid organotin compounds Me-3 and Me-5 were administered once intragastrically to Wistar rats (females) at a MTD of 2000 mg/kg and 750 mg/kg, respectively. Biochemical and morphological studies were carried out on the 7th day of the development of intoxication symptoms according to standard methods.Results. With the introduction of Me-3 and Me-5 in the liver, signs of fatty dystrophy of varying severity were revealed, with a predominant lesion of centrolobular hepatocytes, an increase in the size of portal tracts due to edema and fibrosis, and scant lymphocytic infiltration. With the introduction of Me-5, morphological changes were more severe, with the involvement of the vascular bed of the organ in the process. When the tested compounds were administered in the kidneys, the same type of damage to the glomerular apparatus and renal tubules was recorded, characteristic of toxic nephropathy. Unidirectional changes in the blood of experimental animals were revealed in the group of nonspecific biochemical markers of cytolysis: a moderate decrease in transaminase activity and an increase in the activity of creatine kinase (CC), lactate dehydrogenase (LDH) and creatinine levels. The process of formation of urea and protein synthesis was functionally preserved.Conclusion. On the 7th day of the development of intoxication with a single intragastric administration of hybrid organotin compounds Me-3 and Me-5 in the maximum tolerated doses, biochemical and morphological changes in the body of animals could be attributed to a moderate degree of severity.

Objective : to assess the subchronic toxicity of bis(3,5-di-tert-butyl-4-hydroxyphenyl)dimethyltin (Me-3) and (3,5-di-tert-butyl-4-hydroxyphenyl)triphenyltin (Me-5) with the identification of external signs of toxicity and changes in the indicators of the functional state of the liver and kidneys of Wistar rats (females) with 14-fold daily intragastric injection to simulate a metronomic chemotherapy regimen. Materials and method : the study was conducted on 24 Wistar rats (females) weighing 190-210 g. The tested compounds were administered fourteen times daily intragastrically at a total dose of 2000 mg/kg for Me-3, 954 mg/kg for Me-5. Results : for substances belonging to the class of organic tin derivatives: the features of the toxic process and indicators of the functional state of detoxification organs (liver and kidneys) with subchronic administration were revealed. The injection in total doses amounting to a half-year dose with a fourteen-fold administration did not cause the death of animals and the development of external signs of toxicity, changes in the functional state of the liver and kidneys were not noted. Conclusion : the analysis of the results of the study will allow us to develop optimal schemes for the injection of organotin compounds containing a fragment of 2,6-di-tert-butylphenol in the metronomic regimen.

Objective: to evaluate changes in markers of apoptotic processes and lipid peroxidation (POL) by accumulation of malondialdehyde (MDA) in the mitochondrial fraction of the liver of animals carrying Lewis epidermoid carcinoma at different stages of the tumor process with the introduction of bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethylolol thiolate (Me-3) and (3,5-di-tert-butyl-4-hydroxyphenyl)triphenylololate (Me-5). Materials and methods: the work was performed using laboratory animals - female mice of the C57Bl line/6. 48 hours after the Lewis epidermoid carcinoma strain was transplanted, substances Me-3 and Me-5 were administered once a day for 5 days intraperitoneally at the maximum effective dose of 375 mg/kg and 250 mg/kg, respectively. Animals of the control group were injected with a carrier in similar modes and volumes. Results: when Me-3 was administered at the maximum effective dose on days 7 and 21, a decrease in the level of all the studied indicators was noted, which indicates a high actioxidant activity of a hybrid organotin compound containing one tin-containing [-Sn(CH3)2] and two protective antioxidant fragments (3,5-di-tert-butyl-4-hydroxyphenyl). The compound Me-5 has a more pronounced prooxidant potential, as evidenced by high levels of damage to mitochondrial DNA (8–hydroxy–2'–deoxyguanosine) and malonic dialdehyde. Conclusion: the introduction of bis-(3,5-di-tert-butyl-4-hydroxyphenyl)dimethylolol (Me-3) and (3,5-di-tert-butyl-4-hydroxyphenyl)triphenylolol (Me-5) compounds revealed a change in the pro/antioxidant state and the launch of apoptotic processes in liver cells.

New complexes CuCl 2 [AbAc] 2 ( I ), CoCl 2 [AbAc] 2 ( II ), and ZnCl 2 [AbAc] 2 ( III ) with abiraterone acetate (AbAc) are synthesized. The molecular structure of complex II is determined by X-ray diffraction (XRD) (CIF file CCDC no. 2252346). The cobalt atom coordinates with abiraterone acetate due to the N‑donor pyridine atom. The model processes of hydrolysis of the compounds in acidic and neutral media and their ability to interact with the superoxide radical anion generated in the xanthine–xanthine oxidase enzymatic system are studied. A high activity of complexes I and II is found. The MTT test shows that the antiproliferative activity of compounds I – III against the HCT-116, MCF-7, A-549, and WI-38 cells is comparable with the activity of cisplatin and exceeds that of the initial AbAc for the PC-3 cell line. Complex II also induces cell cycle arrest in the G0/G1 phase of RNA protein synthesis.

The central element of the "metastatic organotropism" is a shift of the pro/antioxidant balance in cells and activation of oxidative stress and protective antioxidant systems. We studied the effects of bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) in the maximum effective and toxic total doses on the level of markers of oxidative stress and antioxidant protection in the liver of mice with melanoma B16 before the appearance of macroscopic metastases. In 48 h after tumor inoculation, Me-3 was administered intraperitoneally once a day for 5 days in total doses of 375 and 500 mg/kg according to the classical method. Administration of the hybrid organotin compound Me-3 produced different effects on the pro/antioxidant state of the microenvironment of liver tissue as the target of melanoma B16 metastasis. The results suggest that inversion of the anti/prooxidant profile of Me-3 is determined by its dose.

The most important task of preclinical research of promising candidates for antitumor drugs is to assess the safety of their use. The study of the cardiotoxicity of organotin compounds (OOS) dimethyltin bis (3,5-di-tert-butyl-4-hydroxy- phenylthiolate) (Me3) and (3,5-di-tert-butyl-4-hydroxyphenylthiolate) triphenyltin (Me5) was carried out with a single intragastric administration at the maximum tolerated dose (MTD) in an experiment on 30 Wistar rats (female) weighing 190-210gr. According to the results of pathomorphological studies and changes in the activity of marker blood enzymes (CK - creatine kinase (EC 2.7.3.2), LDH - lactate dehydrogenase (EC 1.1.1.27), AsAt - aspartate aminotransferase (EC 2.6.1.1), AlAt - alanine aminotransferase (EC 2.6.1.2)), morpho-functional changes were characterized as potentially reversible 14 days after administration of the substances.

Three novel water-soluble tertiary amines with 2,6-di-tert-butylphenol and pyridine fragments were synthesized and characterized. The electrochemical behavior of compounds was studied by cyclic voltammetry, radical scavenging and antioxidant activities were studied. The activity of the compounds towards superoxide radical-anion was estimated. Based on the DPPH and CUPRAC, tests compound with 2-substituted pyridine fragment can act as radical scavenging agent. Antioxidant activity was found to depend on the structure of compounds. Moreover, a prolonged antioxidant activity of compounds was discovered in lipid peroxidation of Russian sturgeon liver homogenate in vitro. High antioxidant activity of amine hydrochloride with 2-substituted pyridine fragment allows one to suggest it for future practical usage as potential pharmacological agent with cytoprotective and antioxidant properties.

We performed a comparative analysis of the pharmacological activity of the hybrid organotin compound bis(3,5-di-tert-butyl-4-hydroxyphenylthiolate)dimethylol (Me-3) administered in different modes to mice with transplanted melanoma B16 to identify the most effective dosage regimen. Three modes of administration were used: preventive (before transplantation of tumor cells), classical according to Z. P. Sof'ina (48 h after transplantation of tumor cells), and delayed (7 days after transplantation of tumor cells, after formation of nodules of the primary tumor node). Compound Me-3 was administered at a total dose of 375 mg/kg intraperitoneally once a day for 5 days. The classical mode of administration was identified as the most effective, which indicates the preventive antimetastatic activity of Me-3 on the model of the transplanted mouse tumor melanoma B16.

The search for new antitumor and antimetastatic therapy targets is a priority task for interdisciplinary research in medical chemistry, experimental pharmacology and pathological physiology. One of the promising scopes of research in this direction is to study the possibility of modifying the polymerization process of tubulin, the main structural component of the microtubules in the cellular cytoskeleton. Various options for influencing microtubules can be used to repurpose already known and develop new antitumor drugs.

Two series of organotin (IV) complexes based on diclofenac (LNa)-Na-1 and aspirin (LH)-H-2 of formulae Me3SnL1 (1); Ph3SnL1 (2); Bu2Sn(L-1)(2) (3); R2Sn(L-1)(2) (4, R = 3,5-di-tert-butyl-4-hydroxyphenyl); Me3SnL2 (5); Me3Sn(2-hydroxybenzoate) (6) and Me2Sn(L-2)(2) (7) were synthesized and characterized by H-1, C-13, Sn-119 NMR, IR, ESI-MS and elemental analysis. It was found by X-ray diffraction analysis of compound 1 that carboxyl group of diclofenac binds two tin atoms each being in the trigonal bipyramid geometry and having coordination number 5. Compounds 6 and 7 were found to be monomers in the solid state with tetrahedron and octahedron geometry around Sn center, respectively. Cytotoxicity in vitro of compounds 1-7 and initial ligands was evaluated on human colon cancer (HCT-116), human breast cancer (MCF-7) and adenocarcinomic human alveolar basal epithelial (A-549) cells. The IC50 values varied in 0.17-200 mu M range for compounds 1-4 and in 3.3-200 mu M range for compounds 5-7 depending on the substituents at Sn center and ligand structure. It was found that compound 2 possesses the maximal cytotoxic activity and significantly induces apoptosis of HCT-116 cells. (C) 2021 Published by Elsevier B.V.

A series of novel imidazole-containing ligands and their organotin complexes were synthesized and characterized by NMR, IR, MALDI and elemental analysis. Redox behavior was studied by cyclic voltammetry (CV). Antioxidant properties were estimated in model reactions of single-electron reduction (CUPRAC-test), scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and O2−. radical anion, enzymatic oxidation of linoleic acid by lipoxygenase and Fe3+-induced lipid peroxidation of rat liver homogenates. It was found that ligands and complexes both possess radical scavenging activity of prolonged action type. Compounds exhibited notable antioxidant activity in lipid peroxidation. Cytotoxicity was estimated in standard MTT-test on multiple cell lines. Compounds demonstrated high toxicity on colon carcinoma and breast cancer cells and based on obtained data, lead compound was proposed. Additional assays were carried out for the lead compound, including regular MTT-test on cancer cells possessing various resistant mechanisms and modified MTT-test on tumor tissue samples, obtained from patients as well as apoptosis and cell cycle studies. All organotin complexes were also studied for their influence on tubulin polymerization. It was demonstrated that obtained compounds demonstrate unorthodox activity, promoting microtubules assembly rate instead of inhibiting it. Significant influence of compound 5 on G2/M phase of cell cycle is in accordance with influence on tubulin polymerization and lets us to mark synthesized compounds as mitotic poisons. The results open up the scopes for the search of novel antitumor agents for treatment of advanced forms of cancer.

The activity towards superoxide anion radical (O 2 ·− ) generated in an enzymatic model system upon reduction of nitro blue tetrazolium (NBT test), as well as during non-enzymatic oxidation of adrenaline in an alkaline media, was revealed for water-soluble quaternary ammonium salts bearing 2,6-di- tert -butylphenol and pyridine moiety. An increased activity of superoxide dismutase of the Russian sturgeon liver homogenate in the presence of these salts was found. A moderate Fe 2+ -chelating activity relative to the EDTA standard is characteristic of these salts. Their inhibitory effect was demonstrated in model systems of non-enzymatic oxidation of cis -octadec-9-enoic acid and lipids of the Russian sturgeon liver homogenate. The highest gross antioxidant activity was found for a water-soluble quaternary ammonium salt containing the ortho -pyridinyl moiety.

This review analyzed the literature data on the in vitro preclinical study of the cytotoxic properties of organotin compounds, as well as the main mechanisms of their action. The latter consist in interacting with SH groups of proteins, initiating oxidative stress, binding to DNA, interacting with receptors, as well as activate apoptosis by increasing the expression of caspases, proapoptotic proteins, and decreasing antiapoptotic proteins. Organotin compounds, depending on the donor ligand, exhibit specifi c cytotoxicity towards certain tumor cell lines. The high cytotoxic potential indicates the possibility of further development in vivo and research of organotin compounds as candidates for the creation of drugs for anticancer and antimetastatic therapy.

Two series of organotin(IV) carboxylates based on phenolic antioxidants RCOOH and R(CH2)(2)COOH (R = 3,5-di-tert-butyl-4-hydroxyphenyl) and natural bile (cholanic) acids of formulae (RCOO)(2)SnMe2 (1); (RCOO)(2)SnBu2 (2); (R(CH2)(2)COO)(2)SnMe2 (3); (R(CH2)(2)COO)(2)SnBu2 (4); (cholate)SnPh3 (5); (deoxycholate)SnPh3 (6); (lithocholate)SnPh3 (7); (cholate)SnMe3 (8); (deoxycholate)SnMe3 (9), and (lithocholate)SnMe3 (10) were synthesized and characterized by H-1, C-13 NMR, IR and elemental analysis to study their antioxidant and cytotoxic potential. Compounds 1 and 2 were found by X-ray diffraction analysis to be monomers in the solid state; moreover, the carboxyl groups are coordinated bidentately through O atoms. The distorted octahedron geometry around the Sn center in the monocrystals of 1, 2 was revealed. The antioxidant activity of compounds as radical scavengers and reducing agents was evaluated in spectrophotometrical tests with stable radical DPPH, reduction of Cu2+ (CUPRAC method) and interaction with superoxide anion radical. Cytotoxicity in vitro of compounds has been estimated on human cancer (colon cancer HCT-116, lung carcinoma A549, breast cancer MCF-7, neuroblastoma SH-SY5Y) cell lines and normal fibroblasts cells. The IC50 values varied in 0.002-100 mu M range for compounds 1-4 depend on the alkyl substituents at Sn center and carboxylate ligand structure. The influence on Fe3+-induced lipid peroxidation, mitochondrial potential and mitochondrial permeability and tubulin assembly have been studied for the compounds 1 and 2. It was shown that the complexes 1 and 2 slightly depolarize the mitochondria but don't influence the calcium-induced mitochondrial permeability transition. Organotin complexes with cholic and deoxycholic acids as ligands were revealed to induce apoptosis in A549 cells. The percentage of apoptotic cells were 27.9 and 27.1% for triphenyltin complexes with cholic and deoxycholic derivatives, respectively. (C) 2019 Published by Elsevier B.V.

The review discusses the latest advances in the directed synthesis and application of macroheterocyclic compounds in science, engineering and technology, viz.as catalysts for various processes in photo-and electrocatalysis, optical chemosensors for metal cations, selective receptors of organic compounds, inductors and selectors, in nonlinear optics, organic electronics, as magnets, photosensitizers for PDT of a number of oncological diseases and for antimicrobial PDT, etc.