Tushar S. Basu Baul

Synthesis and characterization of triorganotin(IV) complexes of 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids. - Crystal and molecular structures of a series of triphenyltin 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoates (aryl=phenyl, 2-methylphenyl, 3-methylphenyl and 4-methoxyphenyl)

Abstract The triphenyltin and tri-n-butyltin complexes of some 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoic acids have been synthesized and characterized by 1H-, 13C-, 119Sn-NMR, IR and 119mSn Mossbauer spectroscopic techniques in combination with elemental analysis. The crystal structures of triphenyltin 5-[(E)-2-(aryl)-1-diazenyl]-2-hydroxybenzoates (aryl=phenyl, 2-methylphenyl, 3-methylphenyl and 4-methoxyphenyl) are reported. Both X-ray and 119Sn Mossbauer data indicate that the triphenyltin complexes adopt a monomeric distorted tetrahedral configuration with the carboxylate ligand coordinating in a monodentate mode. By contrast, 119Sn Mossbauer spectroscopy shows that each tributyltin complex is polymeric and features a trans-trigonal bipyramidal geometry with a planar SnBu3 unit and two apical carboxylate oxygen atoms derived from bidentate bridging carboxylate ligands. This is a solid-state effect, as both 119Sn-NMR and 1J(13C–119/117Sn) coupling constant data indicate tetrahedral geometries in solution for the triphenyl and tri-n-butyl complexes.

The synthesis and structural characterization of some triorganotin(IV) complexes of 2-{[(E)-1-(2-hydroxyaryl)alkylidene]amino}acetic acid. Crystal and molecular structures of Ph3Sn(2-OHC6H4C(H)NCH2COO) and Me3Sn(2-OHC6H4C(CH3)NCH2COO)

Abstract Triorganotin(IV) derivatives of 2-{[(E)-1-(2-hydroxyaryl)alkylidene]amino}acetic acid have been synthesized and characterized by 1H, 13C, 119Sn-NMR, 119Sn Mossbauer and IR spectroscopic techniques in combination with elemental analyses. The crystal structures of triphenyltin 2-{[(E)-1-(2-hydroxyphenyl)methylidene]amino}acetate and trimethyltin 2-{[(E)-1-(2-hydroxyphenyl)ethylidene]amino}acetate are reported. The X-ray structures reveal that the complexes adopt a polymeric trans-O2SnC3 trigonal bipyramidal configuration with the R groups in the equatorial positions and the axial locations occupied by a carboxylate oxygen from the ligand and the phenolic oxygen of the ligand on an adjacent complex. The ligands coordinate in the zwitterionic form with the phenolic proton moved to the nearby nitrogen atom. There is hydrogen bonding between this proton and the phenolic oxygen. The carboxylate group is unidentate. The spectroscopic evidence in combination with 119Sn Mossbauer data suggest that the other complexes adopt similar polymeric structures in the solid state.

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.

Antiproliferative and cytotoxic effect of a novel organotin compound on mammalian cells both in vitro and in vivo

Organotin compounds are organometallic compounds showing various toxicological properties. Several organotin compounds also showed an antineoplastic effect. However, their relative mutagenic potential is not well established. In this study Et(2)SnCl(2).L [L=N-(2-pyridylmethylene)-4-toluidine] (OTC) has been subjected to investigation for its cytotoxic effect in mouse bone marrow cells (BMCs) and human peripheral blood lymphocyte cells (HPBLs). The Sn [bond] N bond in OTC is 2.46A which is greater than 2.39A and therefore, a better formation of tin-DNA complex can be expected. The present data indicate that OTC induced significant delay in cell kinetics and sister chromatid exchanges (SCEs) in both BMCs and HPBLs, whereas, induction of chromosome aberrations was found only in HPBLs. The presence of buthionine sulfoximine (BSO) modulated cellular sensitivity towards OTC in both cell systems. It may be inferred that the OTC could bind on DNA more easily owing to its structural advantage and this may explain the induction of DNA damage and the delay in cell proliferation. Since the cytotoxic effect of OTC is more in glutathione depleted cells, the concentration of OTC may be reduced to get an antitumour effect in GSH-depleted cells and thus minimizes its toxic side effect.

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).

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

SummaryDibutyltin(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.

Triphenyltin(IV) 2-[(E)-2-(aryl)-1-diazenyl]benzoates as anticancer drugs: synthesis, structural characterization, in vitro cytotoxicity and study of its influence towards the mechanistic role of some key enzymes

SummaryTriphenyltin(IV) complexes of composition [Ph3SnL1H]n (1) and [Ph3SnL2H]n (2) (where L1H = 2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyl]benzoate and L2H = 2-[(E)-2-(4-Hydroxy-5-methylphenyl)-1-diazenyl]benzoate) were synthesized and characterized by spectroscopic (1H, 13C and 119Sn NMR, IR, 119Sn Mössbauer) techniques in combination with elemental analysis. The molecular structures and geometries of the complexes (1 and 2) were fully optimized using the quantum mechanical method (PM3). Complexes (1 and 2) were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumour cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The test compounds 1 and 2 exhibit comparable results and both the compounds are found to be far superior to CCDP (cisplatin), 5-FU (5-fluorouracil) and ETO (etoposide) across a panel of cell lines and the activity is more pronounced for the A498 (22 fold) and H226 (33 fold) cell lines compared to CCDP, and A498 (13 fold), H226 (39 fold) and MCF-7 (33 fold) cell lines compared to ETO. The test compounds are even 23 fold more active in magnitude in terms of the ID50 value at least against the H226 cell lines when compared with MTX (methotrexate). Further, the mechanistic role of cytotoxic activity of test compounds (1 and 2), are discussed in relations to the theoretical results of docking studies with some of the key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II.

Synthesis, crystal structures, cytotoxicity and qualitative structure–activity relationship (QSAR) of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes, nBu2Sn(L)2

A series of cis-bis{5-[(E)-2-(aryl)-1-diazenyl]quinolinolato}di-n-butyltin(IV) complexes has been synthesized and characterized by (1)H-, (13)C-, (119)Sn NMR, ESI-MS (electrospray ionization mass spectrometry), IR and (119m)Sn Mössbauer spectroscopic techniques in combination with elemental analyses. The structures of four di-n-butyltin(IV) complexes, viz., (n)Bu(2)Sn(L(3))(2) (3), (n)Bu(2)Sn(L(4))(2) (4), (n)Bu(2)Sn(L(5))(2) (5) and (n)Bu(2)Sn(L(7))(2).0.5C(6)H(6) (7) (LH=5-[(E)-2-(aryl)-1-diazenyl)quinolin-8-ol) were determined by single crystal X-ray diffraction. In general, the complexes were found to adopt a distorted cis-octahedral arrangement around the tin atom. These complexes retain their solid-state structure in non-coordinating solvent as evidenced by (119)Sn and (13)C NMR spectroscopic results. The in vitro cytotoxicity of di-n-butyltin(IV) complexes (3-8) is reported against seven well characterized human tumour cell lines. The basicity of the two quinolinolato donor N and O atoms of the ligands are discussed in relation to the cytotoxicity data.

Synthesis and characterization of diorganotin(IV) complexes of N-(2-pyridylmethylene)arylamines and mutagenicity testing in vivo of Et2SnCl2·[L4=N-(2-pyridylmethylene)-4-toluidine]

Diorganotin(IV) dichloride complexes of the type R 2 SnCl 2 .L (R = methyl, ethyl, vinyl, t-butyl, n-butyl or phenyl; L=N-(2-pyridylmethylene)arylamine) have been synthesized and characterized on the basis of IR, NMR and 119 Sn Mossbauer studies. Investigation of the complexes indicated that N-(2-pyridylmethylene)arylamines form distorted trans-octahedral complexes with R 2 SnCl 2 similar to the well-known R 2 SnCl 2 .L. Cytogenetic toxicology testing has been performed for Et 2 SnCl 2 .L 4 [L 4 = N-(2-pyridylmethylene)-4-toluidine] in mouse bone-marrow cells in vivo since such testing is a regulatory requirement before new drugs are released. This tin compound induced delay in cell-cycle kinetics and sister chromatid exchanges (SCEs) significantly. The effect of Et 2 SnCl 2 .L 4 was greater when endogenous glutathione (GSH) was depleted by buthionine sulphoximine (BSO). It seems that Et 2 SnCl 2 .L 4 induces SCEs due to formation of adduct by binding on DNA which could interfere in DNA synthesis and cause delay in cell proliferation. Depletion of GSH could reduce the shielding effect of GSH on chromatin and allows more Et 2 SnCl 2 .L 4 to bind on DNA.

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.