Organotin(IV) complexes of NSAID, ibuprofen, X-ray structure of Ph3Sn(IBF), binding and cleavage interaction with DNA and in vitro cytotoxic studies of several organotin complexes of drugs

This study encompasses the synthesis and characterization of organotin(IV) derivatives of non-steroidal anti-inflammatory drug ibuprofen (IBF), viz. [(Me3Sn)(IBF)] (1), [(Bu3Sn)(IBF)] (2), [Ph3Sn(IBF)] (3), {[Me2Sn(IBF)](2)O}(2) (4) and [Bu2Sn(IBF)(2)] (5). The crystal structure of complex 3, [Ph3Sn(IBF)], indicates a highly distorted tetrahedral (td) geometry with anisobidentate mode of coordination of the carboxylate group with tin atom, and a similar structure has been proposed for other two triorganotin(IV) derivatives. Moreover, the DFT (density functional theory) calculation and other studies have verified a dimer distannoxane type of structure for complex 4, {[Me2Sn(IBF)](2)O}(2). Complex 5 has been found to exhibit a highly distorted octahedral geometry around the tin atom. To investigate the DNA binding profile of the synthesized complexes, viscosity measurement, UV-vis and fluorescence titrations were performed, which revealed an intercalative type of binding with DNA for IBF and complex 5 and external binding in case of the complexes 1 and 2; complexes 3 and 4 could not be studied owing to their insufficient solubility in tris buffer. Plasmid DNA fragmentation studies of IBF and complexes 1, 2 and 5 indicate that they cleaved the pBR322 plasmid potentially. Further, the drugs IBF {2-[4-(2-methylpropyl)phenyl]propanoic acid}, MESNA (sodium 2-mercaptoethane-sulfonate), warfarin [2H-1-benzopyran-2-one,4-hydroxy-3-(3-oxo-1-phenylbutyl)], sulindac (2-{5-fluoro-1-[(4-methanesulfinylphenyl) methylidene]-2-methyl-1H-inden-3-yl}acetic acid) and their corresponding organotin(IV) complexes 1-19 (complexes 6-19 were synthesized/reported previously) were screened in vitro for cytotoxicity against human cancer cell lines viz. DU145 (prostate cancer), HCT-15 (colon adenocarcinoma), Caco-2 (colorectal adenocarcinoma), MCF-7 (mammary cancer), LNCaP (androgen-sensitive prostate adenocarcinoma) and HeLa (cervical cancer), through MTT reduction assay and the cause of cell death was investigated through acridine orange/ethidium bromide staining of cells and DNA fragmentation assay. The probable structure-cytotoxicity relationship is also discussed. The major role of apoptosis along with small necrosis was also validated by flow cytometry assay using annexin V-fluorescein isothiocyanate and propidium iodide analysis.