Aqua-(2-formylbenzoato)triphenyltin(IV) induces cell cycle arrest and apoptosis in hypoxic triple negative breast cancer cells.

Hypoxia plays a vital role in tumor microenvironment by allowing development and maintenance of cancer cells thereby led to major hindrance for effective anticancer therapy and main reason for failure of most anticancer drugs. We herein investigated the therapeutic efficacy and molecular mechanism of action of aqua-(2-formylbenzoato) triphenyltin (IV) compound (OTC) in MDA-MB-231 cell line. Cobalt chloride induced hypoxic MDA-MB-231 cells treated with OTC were used to access cytotoxicity, ROS, cellular apoptosis, and cell cycle progression. Further, expression of HIF-1α and VEGF, as well as apoptotic proteins like p53, Bax, Bcl-2 and caspase 3 were assessed. The findings indicated that OTC is more effective towards CoCl2 induced hypoxic cells when compared to normoxic cells and the results are far superior to doxorubicin. Additionally, our study revealed that OTC facilitates more ROS production induced cell cycle arrest and promote apoptosis. Furthermore, OTC significantly down regulates the expression of Hif-1α, VEGF and Bcl-2 in hypoxic condition and elevates the level of p53, Bax, cytochrome-C and Caspase 3. Our in vitro studies demonstrated that OTC showed better efficacy than doxorubicin, corroborating that OTC could be a promising compound for hypoxic cancer that also display multi drug resistant.

TPGS loaded triphenyltin (IV) micelles induced apoptosis by upregulating p53 in breast cancer cells and inhibit tumor progression in T-cell lymphoma bearing mice.

AIMS: Currently, breast cancer is one of the most frequently diagnosed and the second leading cause of cancer related deaths in women worldwide. Our present study aimed to investigate the major mechanistic effects of micelles (TSD-30-F, TSD-34-F) on breast cancer cells as well as their antitumor efficacy in in vivo DL bearing BALB/c mice. METHODS: Apoptotic death by micelles was investigated by mitochondrial aggregation, membrane potential and DNA fragmentation assay in MCF-7 and MDA-MB-231 cells. Molecular mode of action of micelles were determined by RT-PCR and western blot analysis, drug-ligand interaction was analyzed by in silico methods, while, in vivo antitumor activity was investigated by Kaplen-Meier survival curve, T/C value, body weight and belly size of BALB/c mice. KEY FINDINGS: TSD-30-F and TSD-34-F micelles displayed significant apoptotic induction. At molecular level, TSD-30 and TSD-34 micelles showed up-regulation of p53, Bax, Bak, Caspase-3 and down-regulation of Bcl-2 genes as well as proteins in tested breast cancer cells. In silico analysis revealed that TSD-30 and TSD-34 showed efficient binding affinity with p53, Caspase-3, Bax and Bcl-2 proteins. Significant in vivo antitumor efficacy was exhibited by the micelles formulations by increasing life span with reduced bodyweight and belly size growth pattern in BALB/c mice compared to DTX-F micelles. SIGNIFICANCE: Our results suggest that triphenyltin (IV) micelles could be a very promising therapeutic candidate for treatment of breast cancer patients and occupy a new place in targeted breast cancer therapeutic.

Structural diversity among some dialkyltin(IV) benzoate and related derivatives.

The molecular structures of five diorganotin(IV) carboxylates, (I)-(V), can be categorized into two main well-known structural types for such Sn complexes. One is the mononuclear dialkytin(IV) carboxylates with an [R2Sn(LH)2]-type skew-trapezoidal bipyramid, where the alkyl ligands are in pseudo-axial positions and the O atoms from two asymmetrically coordinated bidentate carboxylate ligands are in the equatorial plane. This structure type is adopted by dibutylbis{(E)-2-hydroxy-5-[(3-methylphenyl)diazenyl]benzoato}tin(IV) cyclohexane hemisolvate, [Sn(C4H9)2(C14H11N2O3)2]·0.5C6H12, (I), dibenzylbis{(E)-5-[(4-bromophenyl)diazenyl]-2-hydroxybenzoato}tin(IV), [Sn(C7H7)2(C13H8BrN2O3)2], (II), and aquadibenzylbis(4-{(E)-[(Z)-4-hydroxypent-3-en-2-ylidene]amino}benzoato)tin(IV) benzene disolvate, [Sn(C7H7)2(C12H12NO3)2(H2O)]·2C6H6, (III), although the latter has an additional water ligand to give a distorted pentagonal bipyramidal coordination geometry in which the carboxylate groups are more symmetrically coordinated to the Sn atom than in (I) and (II). The other structure motif is that of the tetranuclear bis(dicarboxylatotetraorganodistannoxanes), {[R2Sn(LH)]2O}2, which contain an Sn4O2 core decorated with four bridging carboxylate ligands, plus two alkyl ligands at each SnIV centre. The complexes octabutyltetrakis{µ-(E)-4-[(4-hydroxy-3,5-dimethylphenyl)diazenyl]benzoato}di-µ3-oxido-tetratin(IV) ethanol disolvate, [Sn4(C4H9)8(C15H13N2O3)4O2]·2C2H6O, (IV), and octabutyltetrakis{(E)-3-[(2-hydroxybenzylidene)amino]propanoato}di-µ3-oxido-tetratin(IV), [Sn4(C4H9)8(C10H10NO3)4O2], (V), display this motif. The structures obtained correlate with the 1:1 and 1:2 stoichiometric ratios of the dialkyltin(IV) and carboxylic acid starting materials in the syntheses. The supramolecular structures arising from consideration of secondary Sn...O interactions and/or classic hydrogen bonds include discrete molecules for (V), centrosymmetric dimers for (I), extended chains for (II) and (III), and sheets for (IV).

Cytotoxic homoleptic Ti(iv) compounds of ONO-type ligands: synthesis, structures and anti-cancer activity.

Eight Ti(iv) compounds 1-8, of the type [Ti(Ln)2] where Ln is a variously substituted dianionic tridentate acylhydrazone, were synthesized by reacting the appropriate hydrazide with 2-hydroxybenzaldehyde or 2'-hydroxyacetophenone and titanium(iv) tetra(isopropoxide) in a 2 : 2 : 1 molar ratio. The solid-state structures of 1-6 and 7·CH2Cl2 were deduced from the single crystal X-ray diffraction data, which indicated that each L2- ligand is fully deprotonated and coordinated to the Ti(iv) cation via the enolic oxygen, the imino nitrogen and the phenolic oxygen atoms (ONO donor set) in an enol tautomeric form, the metal assuming the distorted octahedral geometry. The structures of pro-ligands H2L3 and H2L5 are also reported. All complexes displayed high hydrolytic stability. In vitro cytotoxicity assays towards human ovarian A2780 and colon HT-29 cancer cell lines revealed the activity dependence on the acylhydrazone substituents, with electron-donating groups on the phenolato units enhancing the solubility and promoting cytotoxicity. The lead compound 5 of this study presents IC50 values of 2.5 ± 0.2 and 4.2 ± 0.6 µM for ovarian A2780 and colon HT-29 human cancer cells, respectively.

Triphenylstannyl((arylimino)methyl)benzoates with selective potency that induce G1 and G2/M cell cycle arrest and trigger apoptosis via ROS in human cervical cancer cells.

Metal complexes with organelle specificity and potent but selective cytotoxicity are highly desirable. A novel series of triphenylstannyl 4-((arylimino)methyl)benzoates (2-8) were obtained by the reactions of triphenylstannyl 4-formylbenzoate [Ph3Sn(L1)] 1 with primary aromatic amines. Two representative compounds (10, 11) were also synthesized by reacting aqua-triphenylstannyl 2-formylbenzoate [Ph3Sn(L9)(H2O)] (9) with aniline and p-fluoroaniline, respectively. These compounds were characterized by elemental analysis, IR and 1H, 13C and 119Sn NMR spectroscopy, as well as single-crystal X-ray diffraction for compounds 5, 7-11 and three pro-ligands. The in vitro cytotoxic activities of 1-11 were assessed using the MTT tetrazolium dye assay against HeLa (human cervical) and MDA-MB-231 (breast) cancer cells, with IC50 values revealing high activity. Compared to cisplatin, compounds 1-11 exhibited enhanced cytotoxic efficacy, indicating their potential as potent anticancer agents. Among these, 1 and 5 demonstrated maximum inhibition in HeLa cells, with negligible effect on normal human embryonic kidney (HEK) cells. The combined results of the DCFH-DA dye and Hoechst 33342/PI nuclear staining assays, along with flow cytometry analysis, show that they possess a dual mode of action: They induced apoptotic cell death, attributable to the tin-assisted generation of reactive oxygen species. Cell cycle analyses indicated that compounds 1 and 5 exhibit cell growth inhibition and may cause turbulences in the G1 and G2/M phases.

Triphenyltin(IV) benzoates with diazenyl/imino scaffold exhibiting remarkable apoptosis mediated by reactive oxygen species.

The cytotoxic potency of a series of triphenyltin(IV) compounds of general composition [Ph3Sn(Ln)] (1-6) has been probed in vitro employing MDA-MB-231 (human breast cancer) and HeLa (human cervical cancer) cell lines, where Ln=L1-3; isomeric 2/3/4-{(E)-2-[4-(dimethylamino)phenyl]diazenyl}benzoates and L4-6 are their corresponding isoelectronic imino analogues 2/3/4-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]benzoates. Compounds 1-6 have been characterized by elemental analysis and their spectroscopic properties were studied using IR and NMR (1H, 13C, 119Sn) techniques. The molecular structures of a pro-ligand 2-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]benzoic acid (HL4) and two representative molecules, Ph3Sn(L2) 2 and Ph3Sn(L5) 5, have been determined by X-ray crystallography. Structural analyses of 2 and 5 revealed distorted tetrahedral geometries within C3O donor sets owing to monodentate modes of coordination of the respective carboxylate ligands, close intramolecular Sn…O(carbonyl) interactions notwithstanding. Cytotoxic studies in vitro in MDA-MB-231 and HeLa cell lines revealed high activity, in sub-micromolar range, for all investigated compounds. Among these, 1 and 3 exhibited potent cytotoxicity most effectively towards MDA-MB-231 cells with a IC50 value of 1.19 and 1.44µM, respectively, whereas 5 showed remarkable activity towards HeLa cells with a IC50 value of 0.88µM, yet the series of compounds had minimal cytotoxic effect on normal HEK 293 (human embryonic kidney) cell line. The underlying investigation suggested that the compounds exert potent antitumor effect by elevating intracellular reactive oxygen species generation and cause delay in cell cycle by inhibiting cells at G2/M phase. The results presented herein suggest further development of this class of triphenyltin(IV) compounds-based drugs as potential anti-cancer therapies should be pursued.

New dibutyltin(IV) ladders: Syntheses, structures and, optimization and evaluation of cytotoxic potential employing A375 (melanoma) and HCT116 (colon carcinoma) cell lines in vitro.

Synthesis and spectroscopic properties of seven new dibutyltin(IV) compounds of 2-{(E)-4-hydroxy-3-[(E)-4-(aryl)iminomethyl]phenyldiazenyl}benzoic acids (LnHH'; n=2-8) with general formula {[Bu2Sn(LnH)]2O}2 (1-7) are reported. The compounds were characterized by elemental analysis and by UV-Visible, fluorescence, IR, 1H, 13C and 119Sn NMR spectroscopies. Solid state structures of dibutyltin(IV) compounds 1-3, 6 and 7 were accomplished from single crystal X-ray crystallography which reveal the common ladder-type structure with two endo- and two exo-Sn atoms. The redox properties of LnHH' (n=2-4, 7 and 8) and their diorganotin(IV) compounds 1-3, 6 and 7 were also investigated by cyclic voltammetry. In general, the dibutyltin(IV) derivatives exhibited significant in vitro cytotoxic potency towards A375 (melanoma) and HCT116 (colon carcinoma) cell lines as determined by several experiments, like Live and Dead assay, MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay, LDH (lactate dehydrogenase), cleavage of caspases and PARP (poly(ADP-ribose)polymerase), and DNA fragmentation. Dibutyltin(IV) compounds increase cell death without cytolysis and decreases membrane fluidity, without interfering with p53. Among the dibutyltin(IV) compounds, compound 6 was found to be the most potent, with an IC50 value of 78nM. A mechanism of action for tumor cell death is proposed.

Synthesis, photophysical properties and structures of organotin-Schiff bases utilizing aromatic amino acid from the chiral pool and evaluation of the biological perspective of a triphenyltin compound.

Five new organotin(IV) complexes of compositions [Me2SnL1] (1), [Me2SnL2]n (2), [Me2SnL3] (3), [Ph3SnL1H]n (4) and [Ph3SnL3H] (5) (where L1=(2S)-2-((E)-((Z)-4-hydroxypent-3-en-2-ylidene)amino)-3-(1H-indol-3-yl)propanoate, L2=(2S)-(E)-2-((2-hydroxybenzylidene)amino)-3-(1H-indol-3-yl)propanoate and L3=(2S)-(E)-2-((1-(2-hydroxyphenyl)ethylidene)amino)-3-(1H-indol-3-yl)propanoate were synthesized and spectroscopically characterized. The crystal structures of 1-4 were determined. For the dimethyltin derivative 2, a polymeric chain structure was observed as a result of a long Sn∙∙∙O contact involving the exocyclic carbonyl oxygen-atom from the tridentate ligand of a neighboring Sn-complex unit. The tin atom in this complex has a distorted octahedral coordination geometry, in which the long Sn-O bond is almost trans to the tridentate ligand nitrogen-atom. In contrast, the dimethyltin(IV) complexes 1 and 3 displayed discrete monomeric structures where the tin atom has distorted trigonal-bipyramidal geometry with the two coordinating L oxygen atoms defining the axial positions. On the other hand, 4 is a chain polymer in the solid state. The ligand-bridged Sn atoms adopt a trans-Ph3SnO2 trigonal-bipyramidal configuration with equatorial phenyl groups. A carboxylato oxygen atom from one and the hydroxyl oxygen of the successive ligand in the chain occupy the axial positions. The solution structures were predicted by the use of 119Sn NMR chemical shifts. The photophysical properties of the complexes were investigated in the solid and in solution. The triphenyltin(IV) compound 4 was tested in detail ex vivo against A375 (human melanoma) cell line, exhibiting an IC50 value of 261nM to induce cell death as assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay without significant alteration of cytolysis as determined by lactate dehydrogenase (LDH) assay. Compound 4-mediated potent cell death was also determined by Live and Dead assay and caspase-mediated cleavage of poly-ADP ribose polymerase (PARP). Potent cell death activity was not observed in primary cells, like blood-derived peripheral mononuclear cells (PBMC). Compound 4 inhibited the diphenyl hexatriene (DPH) binding to cells and decreased the micro viscosity in a dose-dependent manner. Additionally, the ability of 4 and cyclodextrin (CD) to interact was determined by molecular modelling.

π-π stacking motifs in dialkylbis{5-[(E)-2-aryldiazen-1-yl]-2-hydroxybenzoato}tin(IV) complexes.

The diorganotin(IV) complexes of 5-[(E)-2-aryldiazen-1-yl]-2-hydroxybenzoic acid are of interest because of their structural diversity in the crystalline state and their interesting biological activity. The structures of dimethylbis{2-hydroxy-5-[(E)-2-(4-methylphenyl)diazen-1-yl]benzoato}tin(IV), [Sn(CH3)2(C14H11N2O3)2], and di-n-butylbis{2-hydroxy-5-[(E)-2-(4-methylphenyl)diazen-1-yl]benzoato}tin(IV) benzene hemisolvate, [Sn(C4H9)2(C14H11N2O3)2]·0.5C6H6, exhibit the usual skew-trapezoidal bipyramidal coordination geometry observed for related complexes of this class. Each structure has two independent molecules of the Sn(IV) complex in the asymmetric unit. In the dimethyltin structure, intermolecular O-H...O hydrogen bonds and a very weak Sn...O interaction link the independent molecules into dimers. The planar carboxylate ligands lend themselves to π-π stacking interactions and the diversity of supramolecular structural motifs formed by these interactions has been examined in detail for these two structures and four closely related analogues. While there are some recurring basic motifs amongst the observed stacking arrangements, such as dimers and step-like chains, variations through longitudinal slipping and inversion of the direction of the overlay add complexity. The π-π stacking motifs in the two title complexes are combinations of some of those observed in the other structures and are the most complex of the structures examined.

Insight into inhibition of the human amyloid beta protein precursor (APP: PDB ID ) using (E)-N-(pyridin-2-ylmethylene)arylamine (LR) models: structure elucidation of a family of ZnX2-LR complexes.

The amyloid beta precursor protein (APP) and its neurotoxic cleavage product amyloid beta (Aß) are a cause of Alzheimer's disease and appear essential for neuronal development and cell homeostasis. Proteolytic processing of APP is influenced by metal ions and protein ligands, however the structural and functional mechanism of APP regulation is not known so far. In this context, molecular modeling studies were performed to understand the molecular behavior of (E)-N-(pyridin-2-ylmethylene)arylamines (LR) with an E2 domain of the APP in its complex with zinc (APP; PDB ID: ). Docking results indeed confirmed that the LR interacts with Zn in the binding site of the protein between two α-helical chains. In view of these findings, LR was further investigated for complexation reactions with Zn(2+) in order to establish the structural models in solution and in the solid state. Five new Zn(2+) complexes of compositions viz. [Zn(Br)2(L2-Me)] (), [Zn(Br)2(L2-OMe)] (), [Zn(i)2(L2-OMe)] (), [Zn(NO3)2(L2-OMe)(H2O)] () and [Zn(L4-Me)2(H2O)2](NO3)2 () were synthesized and their structures were ascertained by microanalysis, IR and (1)H NMR spectroscopy, and single-crystal X-ray diffraction. The zinc atom in complex exhibits a distorted tetrahedral geometry while the crystal structures of complexes and show distorted square pyramidal geometries. The zinc cation in and has an octahedral coordination environment, but in the zinc coordination geometry is less distorted. The Zn(ii) cations take part in one ( and ) or two () 5-membered metallacycles imposed by the NN or NNO chelation modes of LR. The significant intermolecular ππ interactions are also discussed.

Synthesis and characterization of some water soluble Zn(II) complexes with (E)-N-(pyridin-2-ylmethylene)arylamines that regulate tumour cell death by interacting with DNA.

The synthesis and spectroscopic properties of nine water soluble zinc(II) complexes of (E)-N-(pyridin-2-ylmethylene)arylamines (L(n)) with the general formula [Zn(X)2(L(n))] (X = Cl(-), Br(-), I(-); (1-8)) and [Zn(µ-N3)(N3)(L(3))]2 (9) are reported. The complexes were characterized by elemental analysis and their spectroscopic properties were studied using UV-Visible, fluorescence, IR and (1)H NMR spectroscopies. The solid state structures of zinc(II) complexes 2-4 and 6-9 were established by single crystal X-ray crystallography. The majority of the structures are mononuclear with tetra-coordinate zinc centres (2-4, 6 and 7) except where L carries an additional donor atom capable of coordinating zinc (8), in which case the zinc atom has a distorted square pyramidal geometry. The centrosymmetric molecule of [Zn(µ-N3)(N3)(L(3))]2 (9) is binuclear with the zinc atoms in a trigonal bipyramidal coordination environment. In general, the dichlorozinc derivatives 1, 3-5 and 8 exhibited moderately elevated in vitro cytotoxic potency towards the human epithelial cervical carcinoma (HeLa) cell line, with 4 as the best performer (IC50 value of 18 µM). Apoptosis-inducing activity, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, showed that the zinc complexes interacted with DNA and thereby interfered the DNA binding of several transcription factors to its promoter sites, thus inhibiting gene transcription required for the biological activity of cells.

The influence of counter ion and ligand methyl substitution on the solid-state structures and photophysical properties of mercury(II) complexes with (E)-N-(pyridin-2-ylmethylidene)arylamines.

Ten neutral monomeric, dimeric and polymeric mercury(II) complexes of compositions HgX(2)L (3, 8), [HgX(2)L](2) (1, 2, 4-6 and 7), [Hg(NO(3))(2)L](n) (9) and {[Hg(N(3))(2)L](2)}(n) (10) where X = chloride, bromide, iodide, nitrate and azide, and L = (E)-N-(pyridin-2-ylmethylidene)arylamine, are described. Compounds 1-10 were characterized by elemental analyses, and IR and (1)H NMR spectroscopic studies. The solution-state photophysical properties of the complexes are highly dependent on the anions as seen in the fluorescence emission features. Single-crystal X-ray crystallography showed that the molecular complexes can aggregate into larger entities depending upon the anion coordinated to the metal centre. Iodide gives discrete monomeric complexes, chloride and bromide generate binuclear complexes formed through Hg-X-Hg bridges, while nitrate and azide lead to 1D coordination polymers. The significant differences in the observed aggregation patterns of the compounds indicate that the anions exert a substantial influence on the formation of the compounds. A further influence upon supramolecular aggregation is the presence of methyl substituents in L(3) and L(4), which generally enhances the probability of forming supramolecular ππ interactions involving the five-membered C(2)N(2)Hg chelate rings in their crystal structures.

Di-µ-iodido-bis-(iodido-{methyl 4-[(pyridin-2-yl-methyl-idene)amino]-benzoate-κ(2) N,N'}cadmium).

The complete binuclear molecule of the title compound, [Cd2I4(C14H12N2O2)2], is generated by the application of a centre of inversion. The Cd-I bond lengths of the central core are close and uniformly longer than the exocyclic Cd-I bond. The coordination sphere of the Cd(II) atom is completed by two N atoms of a chelating methyl 4-[(pyridin-2-yl-methyl-idene)amino]-benzoate ligand, and is based on a square pyramid with the terminal I atom in the apical position. The three-dimensional crystal packing is stabilized by C-H⋯O and C-H⋯π inter-actions, each involving the pyridine ring.

(2-{[4-(Chlorido-mercur-yl)phen-yl]imino-meth-yl}pyridine-κ(2) N,N')di-iodido-mercury(II) dimethyl sulfoxide monosolvate.

The title dimethyl sulfoxide solvate, [Hg2(C12H9ClN2)I2]·C2H6OS, features tetra-hedrally and linearly coordinated Hg(II) atoms. The distorted tetrahedral coordination sphere is defined by chelating N atoms that define an acute angle [69.6 (3)°] and two I atoms that form a wide angle [142.80 (4)°]. The linearly coordinated Hg(II) atom [177.0 (4)°] exists with a donor set defined by C and Cl atoms. Secondary inter-actions are apparent in the crystal packing with the tetra-hedrally and linearly coordinated Hg(II) atoms expanding their coordination environments by forming weak Hg⋯I [3.772 (7) Å] and Hg⋯O [2.921 (12) Å] inter-actions, respectively. Mercury-containing mol-ecules stack along the a axis, are connected by π-π inter-actions [inter-centroid distance between pyridine and benzene rings = 3.772 (7) Å] and define channels in which the dimethyl sulfoxide mol-ecules reside. The latter are connected by the aforementioned Hg⋯O inter-actions as well as C-H⋯I and C-H⋯O inter-actions, resulting in a three-dimensional architecture.

An in vitro comparative assessment with a series of new triphenyltin(IV) 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with anticancer activities: structural modifications, analysis of efficacy and cytotoxicity involving human tumor cell lines.

Four new triphenyltin(IV) complexes of composition Ph(3)SnLH (where LH=2-/4-[(E)-2-(aryl)-1-diazenyl]benzoate) (1-4) were synthesized and characterized by spectroscopic (((1))H, ((13))C and ((119))Sn NMR, IR, ((119))Sn Mössbauer) techniques in combination with elemental analysis. The ((119))Sn NMR spectroscopic data indicate a tetrahedral coordination geometry in non-coordinating solvents. The crystal structures of three complexes, Ph(3)SnL((1))H (1), Ph(3)SnL((3))H (3), Ph(3)SnL((4))H (4), were determined. All display an essentially tetrahedral geometry with angles ranging from 93.50(8) to 124.5(2)°; ((119))Sn Mössbauer spectral data support this assignment. The cytotoxicity studies were performed with complexes 1-4, along with a previously reported complex (5) in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with the results from other related triphenyltin(IV) complexes (6-7) and tributyltin(IV) complexes (8-11) having 2-/4-[(E)-2-(aryl)-1-diazenyl]benzoates framework. In general, the complexes exhibit stronger cytotoxic activity. The results obtained for 1-3 are also comparable to those of its o-analogs i.e. 4-7, except 5, but the advantage is the former set of complexes demonstrated two folds more cytotoxic activity for the cell line MCF-7 with ID(50) values in the range 41-53 ng/ml. Undoubtedly, the cytotoxic results of complexes 1-3 are far superior to CDDP, 5-FU and ETO, and related tributyltin(IV) complexes 8-11. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of triphenyltin(IV) complexes 1-7 and tributyltin(IV) complexes 8-11 is also discussed against a panel of human tumor cell lines.

Advancement towards tin-based anticancer chemotherapeutics: structural modification and computer modeling approach to drug-enzyme interactions.

Three new triphenyltin(IV) complexes, viz., triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(methoxycarbonyl)phenyl)imino)methyl)phenyl)-diazenyl)benzoate (Ph(3)SnL(2)H: 2), methyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate (Ph(3)SnL(3)H: 3), and triphenylstannyl 2-((E)-(4-hydroxy-3-((E)-((4-(((triphenylstannyl)oxy)carbonyl)phenyl)imino)methyl)phenyl)diazenyl)benzoate ((Ph(3)Sn)(2)L(4)H: 4) were synthesized and characterized by spectroscopic ((1)H, (119)Sn NMR and IR) techniques in combination with elemental analysis. The (119)Sn NMR spectral data were recorded in a non-coordinating solvent and indicate tetrahedral coordination geometry in solution. In the solid state, a single-crystal X-ray diffraction analysis of the dinuclear complex (Ph(3)Sn)(2)L(4)H (4) revealed a monocapped tetrahedral coordination geometry with anisobidentate coordination modes of the carboxylate groups with average bond angles around the Sn atoms of 113.5 and 112.2°, respectively. In vitro cytotoxicity studies were performed with all three complexes 2-4, along with a previously reported parent aquatriphenylstannyl complex, 2-((3-formyl-4-hydroxyphenyl)diazenyl)benzoate (Ph(3)SnL(1)H.OH(2) (1)) across a panel of human tumor cell lines, viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The screening results were compared with those from related triphenyltin(IV) carboxylates containing (i) imino (11-16) and (ii) diazenyl frameworks (1, 5-10). In general, complexes 2-4 exhibited good cytotoxic activity and among them, compound 4 was found to be the best performer, particularly for EVSA-T and MCF-7 cell lines. Additionally, 4 scored better activity than cisplatin (2-15 folds), 5-fluorouracil and etoposide across a panel of cell lines. Docking studies indicated that the diazenyl and imino nitrogen atoms, and the oxygen atoms of triphenyltin ester, methyl ester and phenolic group play an important role for the complexation of the organotin compounds in the active sites of enzymes such as ribonucleotide reductase (pdb ID: 4R1R), thymidylate synthase (pdb ID: 2G8D), thymidylate phosphorylase (pdb ID: 1BRW) and topoisomerase II (pdb ID: 1QZR).

Bis{2-[(E)-(5-tert-butyl-2-hy-droxy-phen-yl)diazen-yl]benzoato}dimethyl-tin(IV).

In the title diorganotin dicarboxyl-ate, [Sn(CH(3))(2)(C(17)H(17)N(2)O(3))(2)], the tin(IV) atom is six-coordinated by four O atoms derived from asymmetrically coordinating carboxyl-ate ligands, and two methyl-C atoms. The resulting C(2)O(4) donor set defines a skew-trapezoidal bipyramid with the Sn-C bonds disposed over the weaker Sn-O bonds. Within each carboxyl-ate ligand, the hydroxyl-H atom forms bifurcated O-H⋯(O,N) hydrogen bonds with carboxyl-ate-O and azo-N atoms. The dihedral angles between the benzene rings in the two ligands are 10.44 (11) and 34.24 (11)°. In the crystal, centrosymmetric dimers are formed through pairs of Sn⋯O inter-actions [2.8802 (16) Å], and the dimers are linked into supra-molecular layers in the ac plane by C-H⋯π inter-actions.

Dibutyltin(IV) complexes containing arylazobenzoate ligands: chemistry, in vitro cytotoxic effects on human tumor cell lines and mode of interaction with some enzymes.

Dibutyltin(IV) complexes of composition Bu2Sn(LH)2, where LH is a carboxylate residue derived from 2-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L¹H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L²H) (2) and 4-[(E)-(4-hydroxy-5-methylphenyl)diazenyl]benzoate (L³H) (3), were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹9Sn NMR, IR, ¹¹9Sn Mössbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer.

Molecular basis of the interaction of novel tributyltin(IV) 2/4-[(E)-2-(aryl)-1-diazenyl]benzoates endowed with an improved cytotoxic profile: synthesis, structure, biological efficacy and QSAR studies.

A series of tributyltin(IV) complexes based on 2/4-[(E)-2-(aryl)-1-diazenyl]benzoate ligands was synthesized, wherein the position of the carboxylate and aryl substituents (methyl, tert-butyl and hydroxyl) varies. The complexes, Bu(3)SnL(1-4)H (1-4), have been structurally characterized by elemental analysis and IR, NMR ((1)H, (13)C, and (119)Sn) and (119)Sn Mössbauer spectroscopy. All have a tetrahedral geometry in solution and a trigonal bipyramidal geometry in the solid-state, except for Bu(3)SnL(4)H (4) that was ascertained to have tetrahedral coordination by X-ray crystallography. Cytotoxicity studies were carried out on human tumor cell lines A498 (renal cancer), EVSA-T (mammary cancer), H226 (non-small-cell lung cancer), IGROV (ovarian cancer), M19 MEL (melanoma), MCF-7 (mammary cancer) and WIDR (colon cancer). Compared to cisplatin, test compounds 1-4 had remarkably good activity, despite the presence of substantial steric bulk due to Sn-Bu ligands. The quantitative structure-activity relationship (QSAR) studies for the cytotoxicity of organotin(IV) benzoates, along with some reference drug molecules, is also discussed against a panel of human tumor cell lines. Molecular structures of the tributyltin(IV) complexes (1-4) were fully optimized using the PM6 semi-empirical method and docking studies performed with key enzymes associated with the propagation of cancer, namely ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II. The theoretical results are discussed in relation to the mechanistic role of the cytotoxic active test compounds (1-4).

Tetrakis(mu2-4-aminobenzoato)di-mu3-oxido-tetrakis[dibutyltin(IV)].

The molecule of the title compound, [Sn(4)(C(4)H(9))(8)(C(7)H(6)NO(2))(4)O(2)], lies about an inversion centre and is a tetranuclear bis(tetrabutyldicarboxylatodistannoxane) complex containing a planar Sn(4)O(2) core in which two mu(3)-oxide O atoms connect an Sn(2)O(2) ring to two exocyclic Sn atoms. Each Sn atom has a highly distorted octahedral coordination. In the molecule, the carboxylate groups of two aminobenzoate ligands bridge the central and exocyclic Sn atoms, while two further aminobenzoate ligands have highly asymmetric bidentate chelation to the exocyclic Sn atoms plus long O...Sn interactions with the central Sn atoms. Each Sn atom is also coordinated by two pendant n-butyl ligands, which extend roughly perpendicular to the plane of the Sn(4)O(10) core. Only one of the four unique hydrogen-bond donor sites is involved in a classic N-H...O hydrogen bond, and the resulting supramolecular hydrogen-bonded structure is an extended two-dimensional network which lies parallel to the (100) plane and consists of a checkerboard pattern of four-connected molecular cores acting as nodes. The amine groups not involved in the hydrogen-bonding interactions have significant N-H...pi interactions with neighbouring aminobenzene rings.