The triphenyltin carboxylate derivative triphenylstannyl 2-(benzylcarbamoyl)benzoate impedes prostate cancer progression via modulation of Akt/FOXO3a signaling.

Prostate cancer (PCa) incidence is surging in United States and other parts of the world. Synthetic and natural compounds have been explored as potential modulators of PI3K/Akt signaling that is known to drive PCa growth. Here, we evaluated the efficacy of a series of triphenyltin (IV) carboxylate derivatives against PCa. From this library, triphenylstannyl 2-(benzylcarbamoyl)benzoate (Ch-319) resulted in reduced viability and induction of cell cycle arrest in PTEN-/- PC3M and PTEN+/- DU145 cells. In parallel, downregulation of PI3K p85/p110 subunits, dephosphorylation of Akt-1 and increase in FOXO3a expression were observed. In silico studies indicated binding interactions of Ch-319 within the ATP binding site of Akt-1 at Met281, Phe442 and Glu234 residues. Elevated po-pulation of apoptotic cells, activation of Bax and reduced Bcl2 expression indicated apoptosis by Ch-319. Pre-sensitization of PCa cells with Ch-319 augmented the effect of cabazitaxel, a commonly used taxane in patients with castration-resistant PCa. Next, in a prostate-specific PTENp-/- mice, Ch-319 showed reduced weights of genitourinary apparatus as compared to DMSO treated controls. Histological studies indicated absence of neoplastic foci in Ch-319 treated prostates. Consistently, dephosphorylation of Akt-1, reduced expression of PRAS40 and androgen receptor and increase in FOXO3a were observed in treated group. Notably, no overt organ toxicity was noted in Ch-319 treated animals. Our studies identify Akt/FOXO3a signaling as a target of triphenyltin (IV) carboxylate Ch-319 and provide a molecular basis of its growth inhibitory effect in PCa cells. We propose that Ch-319 has the potential to be developed as an anticancer agent against PCa.

Antitumor effects of the electromagnetic resonant frequencies derived from the 1H NMR spectrum of Ph3Sn(Mercaptonicotinic)SnPh3 complex.

The aim of this article is to investigate the potential cytotoxic and antitumor effects of the resonant electromagnetic fields (rEMFs) derived from the 1H NMR spectrum of the Ph3Sn(Mercaptonicotinic)SnPh3 complex (SnMNA). The ability of the complex's rEMFs to induce leiomyosarcoma (LMS) cell death and to recess tumor (leiomyosarcoma) development in Wistar rats was evaluated. The effects of the simultaneous administration of the SnMNA complex at extremely low concentrations and exposure to its rEMFs was also investigated. The emission of the 1H NMR spectrum of the complex alone or in a combination with low ineffective doses of the complex decreased LMS cell viability mainly through apoptosis. Moreover, the results from the in vivo experiments showed a significant prolongation of life expectancy in tumor-bearing rats exposed to the rEMFs alongside a deceleration in tumor growth rate. We speculate that the rEMFs of a biologically active substance could exert similar biological effects as the substance itself, mainly when is combined with extremely low ineffective concentrations of the substance.

Anti-proliferative and antitumor activity of organotin(IV) compounds. An overview of the last decade and future perspectives.

Organotins(IV) exhibit significant in vitro anti-proliferative activity, while the in vivo tests are encouraging. The recent reports on the anti-proliferative activity of organotin(IV) compounds are summarized in this review. The period covered by this work goes back to 2009 until late 2018, while the earlier ones, are included over the previous review of our group published by S.K. Hadjikakou, N. Hadjiliadis, in Coord Chem Rev, 253 (2009) 235-249. During the last decade (2009-2018), >300 organotin(IV) derivatives with oxygen-donor ligands, such as carboxylic acids, amino-acids, Non Steroidal Anti-inflammatory Drugs (NSAIDs), biological active derivatives or natural products, organotins(IV) with sulfur containing ligands such as thiones, thiosemicarbazones, dithiocarbamates, organotin(IV) compounds of oximes and organotins(IV) with amines or semicarbazones were screened for their anti-proliferative effect against various cancer cell lines and their results are included in numerous reports over this period. Although much work has been carried out on organotin(IV) derivatives with O-donor ligands, however significant fewer reports are found on organotins(IV) with oximes as ligands.

Organotin(IV) Carboxylates as Promising Potential Drug Candidates in the Field of Cancer Chemotherapy.

Medicinal inorganic chemistry plays an important role in exploring the properties of metal ions for the designing of new drugs. The field has been stimulated by the success of cis-platin, the world best selling anticancer drug and platinum complexes with reduced toxicity, oral activity and activity against resistant tumors are currently on clinical trial. The use of cis-platin is, however, severely limited by its toxic side-effects. This has stimulated chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. The discovery of new non-covalent interactions with the classical target, DNA, was the first developing step in the treatment of cancer. The use of organometallic compounds as a medicine is very common now a days because it offers potential advantages over the more common organic-based drugs. In this article we have highlighted the anticancer activity of the organotin(IV) carboxylates published in the last few years (from 2008 to 2016). In most cases they present lower IC50 values than those of cisplatin, which indicates their high activity against the cancer cell lines. The summarized data reveal that every year new organotin(IV) carboxylate complexes are synthesized with the aim of new anticancer agent with much better results than the than the corresponding activity of cis-platin or other clinically approved drugs. In addition to the advantages of high activity, compared to the platinum compound, tin complexes are much cheaper. Thus by using organotin carboxylate for clinical medicine, cost reduction, dosage reduction and effect enhancement will be reached.

Design and synthesis of (S)- and (R)-enantiomers of [4-(2-hydroxy-1-phenylethylimino)pent-2-ol]dimethyltin(iv) and 2,2-dimethyl-4-phenyl-1,3,2-oxazastannolidine: in vitro antitumor activity against human tumor cell lines and in vivo assay of (S)-enantiomers.

New dimethyltin derived antitumor drug candidates (S)- and (R)-[4-(2-hydroxy-1-phenylethylimino)pent-2-ol]dimethyltin(iv), 1 and (S)- and (R)-[2,2-dimethyl-4-phenyl-1,3,2-oxazastannolidine], 2 derived from (R)- and (S)-enantiomers of [4-(2-hydroxy-1-phenylethylimino)pent-2-ol] and 2-amino-2-phenylethanol, respectively, were synthesized and thoroughly characterized. Preliminary complex-DNA interaction studies employing various optical methods revealed that the (S)-enantiomer displayed a higher propensity towards the drug target DNA double helix. This was quantified by K(b) and K(sv) values of ligands L and L' and (S)-/(R)-1 and (S)-/(R)-2 complexes, which demonstrated a multifold increase in the case of the (S)-enantiomers in comparison to their (R)-enantiomeric forms. This clearly demonstrates the chiral preference of the (S)-enantiomer over the (R)-enantiomer, and its potency to act as a chemotherapeutic agent. Therefore, the in vitro antitumor activity of the (S)-enantiomer of 1 and 2 was evaluated by the sulforhodamine-B (SRB) assay to assess cellular proliferation against five different human cell lines viz., Hop62, DWD, K562, DU145 and MCF-7. The complex (S)-1 displayed a remarkably pronounced and specific activity for K562, while complex (S)-2 exhibited significant activity towards Hop62, DWD, DU145 and MCF-7. The in vivo antitumor activity of (S)-1 and (S)-2 was carried out, which revealed significant regression in human lung tumors.

Cytotoxic and anticancer effects of the triorganotin compound [(C6H5)3Sn(cmbzt)]: an in vitro, ex vivo and in vivo study.

Since the initial success of cisplatin, metal complexes and organometallic compounds have been gaining growing interest in cancer therapy. It is well known that organotin(IV) compounds display strong biological activity. The triorganotin compound [(C(6)H(5))(3)Sn(cmbzt)] (cmbzt=5-chloro-2-mercaptobenzothiazole) (SnCMB), was tested for its antiproliferative and antitumour activities. Two sets of experimental procedures were followed: (1) In vitro and ex vivo procedures included the study of the cytotoxic activity of the complex against leiomyosarcoma cells (LMS) and on a normal human fibroblast line (MRC5) by the MTT assay (cell proliferation), colony formation efficiency and flow cytometric analysis with Annexin V-FITC. The anticoagulation properties of the complex were also studied. (2) In vivo procedures included acute toxicity studies and finally administration of the complex to tumour bearing Wistar rats. The results showed that the complex exhibited potent cytotoxic activity (LMS IC(50)=155 nM) and induced significant apoptosis against LMS cells. Acute toxicity studies on Wistar rats presented kidney and liver toxicity at a single dose of 40 mg/kg body wt. Furthermore, antitumour activity studies on sarcoma bearing Wistar rats revealed that SnCMB complex, administrated in two different therapeutic schemes (treated with 4 × 2 mg/kg body wt every 5 days and 3 × 2.67 mg/kg body wt every 10 days of SnCMB complex), prolonged mean survival time (by 50% and 70% respectively), but failed to decrease the mean tumour growth rate (MTGR) compared to the control group (p<0.01). In conclusion, the organic complex SnCMB possess potent cytotoxic and antimetastatic effects, and low toxicity introducing it as possible successor of organometallic compounds used nowadays in chemotherapy.

Organometallic compounds in oncology: implications of novel organotins as antitumor agents.

Since the introduction of cisplatin in cancer therapy, metal complexes and organometallic compounds have been gaining growing importance in oncology. The impressive clinical effectiveness of cisplatin is limited by significant side effects and the emergence of drug resistance. Thus, novel classic and unconventional Pt(II) and Pt(IV) complexes have been introduced in therapy or are presently in advanced clinical trials. Moreover, innovative non-platinum metal-based antitumor agents, whose activity does not rely on direct DNA damage and may involve proteins and enzymes, have been developed. Gold and tin derivatives are enjoying an increasing interest and appear very promising as potential drug candidates.

Inhibition of hemoxygenase-1 improves survival after liver resection in jaundiced rats.

BACKGROUND: The role of hemoxygenase (HO)-1 after partial liver resection (PLR) in jaundiced animals has yet to be defined. We therefore investigated: (1) the acute effects of bile duct ligation (BDL) on bilirubin accumulation and hepatocellular integrity after PLR; (2) how BDL and PLR affect HO-1 protein expression; (3) how functional HO-1 blockade affects survival and liver regeneration after BDL and PLR. METHODS: Male Sprague-Dawley rats were subjected to BDL or a sham operation. After 3 days, a 70% hepatectomy was performed. In a second set of experiments, BDL animals received either Sn(IV) mesoporphyrin IX dichloride (SnMP) for HO-1 blockade or a vehicle. Three days later, PLR was performed and survival of the animals was observed for 7 days. RESULTS: PLR, BDL and both together cause a hepatocellular injury and HO-1 expression. Inhibition of HO-1 with SnMP in jaundiced rats that underwent PLR was associated with improved survival, attenuated postoperative weight loss and better liver synthesis. CONCLUSION: The present findings add further evidence that the protective properties of increased HO-1 expression largely depend on the model used, and that HO-1 overexpression in the model of liver resection during acute cholestasis may also be detrimental.

In vitro cytotoxic activity of tri-n-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) and preliminary antitumor activity in vivo.

The cytotoxicity in vitro and antitumor activity in vivo of the organotin compound tri-n-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) have been investigated. The IC50 values obtained in a panel of tumor cell lines were compared to those of the parental compound IST-FS 29 in the same cells. IST-FS 35 resulted significantly more active than IST-FS 29 with IC50 values in the range 0.16-1.8 microM. Toxicity studies in vivo, after intravenous administration of escalating concentrations of IST-FS 35, provided the identification of the maximal tolerated dose (3.5 mg/kg) which was employed as therapeutic dose in the antitumor activity experiments. Preliminary results, in transplanted murine tumor models, revealed that both the P388 myelomonocytic leukaemia and the B16-F10 melanoma, implanted subcutaneously in BDF1 mice, were inhibited about 96% in their tumor volume at day 11, following a single intravenous injection of the compound. Additional studies are mandatory to unravel the mechanism of action for the development of IST-FS 35 as potential antitumor drug.

Cell proliferation inhibition and antitumor activity of novel alkyl series of diorganotin(IV) compounds.

Diorganotin(IV) compounds, R2SnCl2 are often tetrahedral, and structurally resemble the active platinum compounds, i.e. cisplatin, and consequently a large number of such complexes have been tested for antitumor activity. A structural correlation with biological activity for diorganotin(IV) complexes has shown that active species are associated with complexes having Sn-N bonds longer than 2.39 A which in turn determines the formation of a tin-DNA complex. In view of these, a series of diorganotin(IV) dichloride complexes of N-(2-pyridylmethylene)arylamine (nitrogen-chelating ligands) has been synthesized and characterized on the basis of IR, NMR and 119Sn-Mössbauer studies. In the present study, an attempt was made to determine the comparative antiproliferative and antitumor effect of diorganotin(IV) complexes with different alkyl groups [Me2SnCl2.L1 (OTC-1), Et2SnCl2.L2 (OTC-2) and (n)Bu2SnCl2.L2 (OTC-3)]. The present study in human lymphocytes demonstrated that these diorganotin(IV) complexes could block the cell cycle progression and induce sister chromatid exchanges (SCEs) significantly, however, with respect to the induction of chromosome aberrations (CAs) it was very mild. Both the levels of p53 and p16 proteins were raised after diorganotin(IV) treatment and such induction was maximum in the OTC-3 treated samples. The antitumor activity was determined in accordance with the US National Cancer Institute (NCI) standard protocol for primary screening in Dalton's lymphoma that was maintained by serial intraperitoneal transplantation. The T/C (treated/control) value was increased (186% with OTC-3) when diorganotin(IV) was given after transplantation. The data suggest that the OTC-3 has better antiproliferative and antitumor activity and endogenous glutathione level has no influence on the effect of OTC-3.

Antiparasitic activity of a triphenyl tin complex against Leishmania donovani.

Visceral leishmaniasis is a life-threatening human disease commonly known as kala-azar. Leishmania donovani is the causative agent of this parasitic disease transmitted by the sand fly vector to infect hosts. Triphenyl tin salicylanilide thiosemicarbazone [Ph(3)Sn(OSal.TSCZH)] (TTST) which is an organometallic complex of triphenyl tin has been evaluated to explore possibility to develop a potent chemotherapeutic agent against visceral leishmaniasis. Effect of triphenyl tin complex on growth inhibition and host--parasite interaction were examined both in vitro and in vivo. Release of toxic superoxide radical was measured spectrophotometrically through the formation of blue formazan derived from reduced nitrobluetetrazolium. To understand mode of action of Ph(3)Sn(OSal.TSCZH), superoxide dismutase activity was determined spectrophotometrically by measuring ability of this enzyme to inhibit pyrogallol autoxidation and also by activity staining of the non-denaturing polyacrylamide gels after separating superoxide dismutase. Antileishmanial activity of triphenyl tin complex were found to be effective both in vitro and in vivo at lower concentrations compared to the existing toxic drugs available. IC(50) of Ph(3)Sn(OSal.TSCZH) was calculated as 0.05+/-0.01mg/L. Intracellular survival of the parasite in host macrophages was inhibited by TTST in a dose dependent manner. Parasite burden in spleen was reduced to 87% under TTST treatment (10mg/kg body weight) and under sodium antimony gluconate (20mg/kg body weight) reduced nearly to 65%. Its action as a chemotherapeutic agent is found to be mediated through inhibition of superoxide dismutase and simultaneous release of toxic superoxide radical. We propose that Ph(3) Sn(OSal.TSCZH) may be considered as a prospective candidate to establish a better line of therapeutic process against experimental visceral leishmaniasis.

Cytotoxicity in vitro and preliminary antitumor activity in vivo of a novel organotin compound.

The cytotoxic effect and antitumor activity induced by the novel organotin compound triethyltin(IV)lupinyisulfide hydrochloride, have been investigated. Different patterns of antiproliferative effects have been observed in a panel of human tumor cell lines in vitro. Toxicity studies in mice reported acute toxicity at the doses of 21 and 17.5 mg/kg which progressively disappeared at lower concentrations. On this basis, the doses of 3.5, 7 and 14 mg/kg were selected to assess the antitumor activity in vivo against the P388 leukemic cells xenografted in mice. This compound was able to induce a dose-dependent significant reduction of tumor volume, up to 46%, at the highest concentration (p = 0.0062) without important toxicity, as also confirmed by histological analysis of the main organ tissues. This preliminary study seems to hold interest for further investigations in different tumor models as well as for the evaluation of optimal drug route and schedule.

Trypanocidal activity of organotin chlorides on Trypanosoma brucei-infected mice.

The organotin compounds dibutyltin (DBTC) and diphenyltin dichlorides (DPTC) were tested for trypanocidal activity on a Trypanosoma brucei-infected mice model. At a dose of 10 mg DBTC and 15 mg DPTC/kg/day for five consecutive days, they cleared the parasites from the peripheral blood of the infected mice. Subinoculation of some healthy mice with the homogenates of liver, spleen, kidney, cerebrospinal fluid and blood from the mice considered cured, showed a few cases of relapse. The LD50 of DBTC and DPTC are 90 mg/kg and 75 mg/kg respectively.

[Tin compounds in pharmacy and nutrition]. / Az ón és ónorganikus vegyületek szerepe a gyógyászatban és a táplálkozásban.

The occurrence of tin in plants, animals and humans is discussed, in relation to its abundance in the lithosphere and hydrosphere and the range of the different tin(II) and tin(IV) complexes formed. A reasoned consideration of its essentiality for living species is provided. It is concluded that tin is beneficial, even if not yet proved to be an essential element. After reference to the chemistry of tin compounds, there is a detailed discussion of their toxicity in animals and humans. Feasible routes for tin intake and uptake into humans are described. The past and current use of tin pharmaceuticals is reviewed and the areas for which they are currently permitted for use in humans as dentifrices and mouth washes, as radio-pharmaceuticals and for the treatment of jaundiced newborns are described. A detailed review of tin-containing antitumour agents as representative tin pharmaceuticals is also given. Finally, a list of tin-containing drugs and drug candidates is also shown.

Crystal and molecular structure and in vitro antiproliferative and antitumor activity of two organotin (IV) carbohydrate compounds.

3-C-[(Triphenylstannyl)methyl]-1,2:5,6-di-O-isopropylidene-alpha-D -allofuranose (Ph3SnCH2 carbohydrate) and 3-C-(triphenylstannyl)-1,2:5,6-di-O-isopropylidene-alpha-D-allo furanose (Ph3Sn carbohydrate) were studied by diffraction methods, space groups P2(1)2(1)2(1), a = 6.073 (1), b = 13.091 (3), c = 37.739 (13) and a = 8.3219 (9), b = 11.876 (1), c = 29.575 (5) A, respectively; both compounds have distorted tetrahedral coordination. The biological study of these compounds along with Ph3SnCl shows the following: (a) With respect to their capacity to interfere with DNA, RNA, and protein synthesis of isolated fastly proliferating thymocytes, the triphenyltin carbohydrates are less active than Ph3SnCl. Protein synthesis was found to be most sensitive with an IC50 value of approximately 0.3 microM for Ph3SnCl, 3 microM for Ph3Sn-carbohydrate, and greater than 5 microM for Ph3SnCH2-carbohydrate; (b) The in vitro activity toward the mouse tumor cell lines MOPC315, P815, SL2, and L1210, which was also performed for Bu2SnCl2, also showed that the two triphenyltin carbohydrates were less effective than Ph3SnCl. From these results it is concluded that in vitro these Sn-C bonded triphenyltin carbohydrates are less active than Ph3SnCl. Ph3Sn carbohydrate is more active than Ph3SnCH2 carbohydrate, and this may be related with the long Sn-C (of the carbohydrate moiety) bond distance (2.225 (8) A) for the former compound. This compound shows a biological activity which is in contrast to the normal inactivity of tetraorganotins and is the first active member of this family whose molecular structure is reported.

The acute toxicity and in vivo antitumour activity against L1210 leukemia of triphenyltin 3,5-diisopropylsalicylate, bis (di-n-butyl-(s)-2-pyrrolidone-5-carboxylato)tin oxide and di-n-butyltin bis(3-amino-4-methylbenzoate).

Triphenyltin 3,5-di-isopropylsalicylate, compound 1, is characterized by a maximum tolerated dose (MTD) of 20 mg/kg. Bis[di-n-butyl(2-pyrrolidone-5-carboxylato)tin] oxide, compound 2, and (di-n-butyltin bis(3-amino-4-methyl-benzoate), compound 3, exhibit similar acute toxicities (MTD = 8 mg/kg) despite their lower in vitro activity, as compared to compound 1, against the two human tumor cell lines MCF-7 and WiDr. All three are inactive in vivo against L1210 leukemia in mice.

In vitro cytotoxicity of diorganotin (IV) trimethoxy-benzoates against sixty human NCl tumor cell lines.

Diethyl- and di-n-butyltin (IV) trimethoxybenzoates were tested in vitro at the National Cancer Institute, Bethesda, Maryland, USA, for cytotoxic activity against a panel of 60 human cell lines. The di-n-butylin compounds are more active in vitro against human tumor cell lines than their diethyltin analogs.

Antitumor organometallics. I. Activity of some diphenyltin(IV) and diphenylantimony(III) derivatives on in vitro and in vivo Ehrlich ascites tumor.

Diphenyltin(IV) and diphenylantimony(III) derivatives of dithiophosphorus ligands, i.e. Ph2Sn(S2PPh2)2 (1), Ph2Sn[S2P(OPr)2]2 (2), Ph2SbS2PPh2 (3) and Ph2SbS2P(OPri)2 (4), have been tested in vitro and in vivo against Ehrlich ascites tumor. All four compounds were almost equally effective in vitro, exhibiting inhibitory effects on cell proliferation, viability and protein synthesis, and exacerbated respiration and Ca-ATPase activity. In mice bearing Ehrlich ascites tumor cells, all four compounds inhibited the tumor growth, the organometallic phosphorodithioates being more active than phosphinodithioate analogues, and the organoantimony derivatives more active than organotins. Compound 4 (5 mg/kg/day, i.p., on days 1,3 and 5) produced an increase in life span of 83% and a cure rate of 30% in mice bearing this tumor.

Efficacy of different anticoccidials against experimental coccidiosis in large white turkeys.

Two trials were conducted to compare the efficacy of currently approved anticoccidials for turkeys against challenge using a field isolate of mixed Eimeria species; E. adenoides, E. gallopavonis, and E. meleagrimitis. Poults in wire-floored cages were fed unmedicated diets from day-old to 3 wk of age. Diets were supplemented with either amprolium (AMP, 125 mg/kg), butynorate (BUT, 375 mg/kg), monensin (MON-60, 60 mg/kg; MON-100, 100 mg/kg), halofuginone (HAL; 3 mg/kg), zoalene (ZOA; 125 mg/kg), or sulfadimethoxine plus ormetoprim (SUL + ORM, 62.5 mg/kg and 37.5 mg/kg, respectively). After 2 days on the test diets, poults were individually weighed and inoculated with sporulated coccidial oocysts from the field isolate. Total fecal collections were obtained for Days 0 to 5 and 6 to 10 to estimate oocyst output. At 10 days postinoculation, the birds were individually weighed and killed to determine severity of intestinal lesions. The HAL and MON were most effective and AMP, ZOA, and SUL + ORM were least effective in maintaining weight and in reducing the severity of intestinal lesions. All the coccidiostats tested reduced oocyst passage, but poults fed HAL produced fewer oocysts. The results demonstrated differences in efficacy among anticoccidials with the more recently approved drugs providing the best protection against coccidiosis.