A series of alkenyl-substituted titanocene compounds have been supported on the mesoporous silica-based material KIT-6. The corresponding functionalised materials were completely characterised by different techniques (solid-state multinuclear NMR spectroscopy, IR spectroscopy, N2 adsorption-desorption isotherms, X-ray fluorescence and diffraction, SEM and TEM) to observe the incorporation of the titanocene derivatives on the external surface of the material KIT-6. Both the titanocene compounds and the materials were tested in vitro against a wide variety of human cancer and normal cell lines. A very high cytotoxicity of the synthesised titanocene derivatives (IC50 values in the range of those described in the literature for the most active cytotoxic titanocene compounds), with selectivity towards cancer cell lines was observed. The cytotoxic activity of the materials is the highest reported to date for titanocene-functionalised materials. In addition, higher Ti uptake (from 4 to 23% of the initial amount of Ti) of the cells treated with materials was observed with respect to those treated with "free" titanocene derivatives (which gave Ti uptake values from 0.4 to 4.6% of the initial amount of Ti). Additional experiments with the titanocene derivatives and the functionalised materials revealed that changes to the morphological and functional dynamics of apoptosis occurred when the active titanocene species were incorporated into mesoporous materials. In addition, the materials could induce programmed cell death in tumour cell populations by impairing the damaged DNA repair mechanisms and by upregulation of intrinsic and extrinsic apoptotic signalling pathways.
A group of organotin(IV) complexes were prepared: [SnCy3 (DMNI)] (1), [SnCy3 (BZDO)] (2), [SnCy3 (DMFU)] (3), and [SnPh2 (BZDO)2 ] (4), for which DMNIH=2,6-dimethoxynicotinic acid, BZDOH=1,4-benzodioxane-6-carboxylic acid, and DMFUH=2,5-dimethyl-3-furoic acid. The cytotoxic activities of compounds 1-4 were tested against pancreatic carcinoma (PANC-1), erythroleukemia (K562), and two glioblastoma multiform (U87 and LN-229) human cell lines; they show very high antiproliferative activity, with IC50 values in the 150-700 nM range after incubation for 72 h. Distribution of cellular DNA upon treatment with 1-4 revealed that whereas compounds 1-3 induce apoptosis in most of the cell lines, compound 4 does not affect cell viability in any cell line tested, indicating a possible difference in cytotoxic mechanism. Studies with the daunomycin-resistant K562/R cell line expressing P-glycoprotein (Pgp) showed that compounds 1-4 are not substrates of this protein efflux pump, indicating that these compounds do not induce acquisition of multidrug resistance, which is associated with the overexpression of Pgp.
The synthesis of the ether-substituted group 4 metallocene complexes [Ti(η 5 -C 5 H 5 )(η 5 -C 5 H 4 {CMeRCH-(OMe) 2 })Cl 2 ] (R = Me (4), Ph (5)) and [M(η 5 -C 5 H 4 {CMeRCH(OMe) 2 }) 2 Cl 2 ] (M = Ti, R = Me (6), Ph (7); M = Zr, R = Me (8), Ph ( 9)) is reported. In addition, the titanocene derivatives 4−7 have been supported on the mesoporous silica-based material KIT-6, giving the functionalized materials K4−K7, respectively. All compounds and materials have been characterized by different analytical techniques such as solution NMR spectroscopy, mass spectrometry, elemental analysis, solid-state multinuclear NMR spectroscopy, IR spectroscopy, N 2 adsorption− desorption isotherms, X-ray fluorescence and diffraction, SEM, and TEM. Additionally, the molecular structures of the zirconocene derivative 8 and the hydrolysis product [Ti(η 5 -C 5 H 5 )(η 5 -C 5 H 4 {CMe 2 COO})Cl] (4a) of titanocene complex 4 have been determined by X-ray diffraction studies. The structure of 4a reveals a five-membered metallacyclic arrangement. The ether-substituted titanocene compounds 4−6 and the functionalized material K5 have been tested for their antiproliferative and cytotoxic effects in vitro in three human cancer cell lines (A549 lung adenocarcinoma, MCF-7 breast adenocarcinoma, and HCT-116 colorectal adenocarcinoma), as well as in normal human fibroblasts. Compounds 4−6 and K5 showed moderate but specific cytostatic effects. Moreover, additional studies related to the hydrolytic stability (for 4−7) and DNA interaction (for 6) have been carried out. Finally, taking into account the feasible applicability of metallocene complexes, a preliminary ethylene polymerization study has been performed using the two synthesized zirconocene compounds (8 and 9).
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