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.

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).