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
Kumari, R; Banerjee, S; Roy, P; Nath, M
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.