Anticancer Tungstenocenes with a Diverse Set of (O,O-), (O,S-) and (O,N-) Chelates-A Detailed Biological Study Using an Improved Evaluation via 3D Spheroid Models.

The synthesis, characterization and biological activity of tungstenocenes with varying biologically active (O,O-), (S,O-) and (N,O-) chelates are described. Complexes were characterized by 1H and 13C NMR, elemental analysis, ESI-mass spectrometry, FT-IR spectroscopy and X-ray diffraction analysis. The aqueous stability was studied by UV/Vis spectroscopy and the WIV to WV process by cyclic voltammetry. The cytotoxicity was determined by the MTT assay in A549, CH1/PA-1 and SW480 cancer cells as well as in IMR-90 human fibroblasts. Extensive biological evaluation was performed in three other human cancer cell lines (HCT116, HT29 and MCF-7) in monolayer and multicellular tumor spheroid cultures to better understand the mode of action. Lead compounds showed promising in vitro anticancer activity in all cancer cell lines. Further studies yielded important insights into apoptosis induction, ROS generation, different patterns in metal distribution (detected by LA-ICP-TOF-MS), changes in KI67 (proliferation marker) expression and DNA interactions. The results based on qualitative and quantitative research designs show that complexes containing (S,O-) chelates are more active than their (O,O-) and (N,O-) counterparts. The most striking results in spheroid models are the high antiproliferative capacity and the different distribution pattern of two complexes differing only in a W-S or W-O bond.

Highly Cytotoxic Molybdenocenes with Strong Metabolic Effects Inhibit Tumour Growth in Mice.

A series of six highly lipophilic Cp-substituted molybdenocenes bearing different bioactive chelating ligands was synthesized and characterized by NMR spectroscopy, mass spectrometry and X-ray crystallography. In vitro experiments showed a greatly increased cytotoxic potency when compared to the non-Cp-substituted counterparts. In vivo experiments performed with the dichlorido precursor, (Ph2 C-Cp)2 MoCl2 and the in vitro most active complex, containing the thioflavone ligand, showed an inhibition of tumour growth. Proteomic studies on the same two compounds demonstrated a significant regulation of tubulin-associated and mitochondrial inner membrane proteins for both compounds and a strong metabolic effect of the thioflavone containing complex.

The First Anticancer Tris(pyrazolyl)borate Molybdenum(IV) Complexes: Tested in Vitro and in Vivo-A Comparison of O,O-, S,O-, and N,N-Chelate Effects.

The synthesis, characterization and biological activity of molybdenum(IV) complexes containing Trofimenko's scorpionato ligand, hydrotris(3-isopropylpyrazolyl)borate (TpiPr ), in addition to varying biologically active as well as other conventional ligands is described. Ligands employed include (O,O-) (S,O-) (N,N-) donors that have been successfully coordinated to the molybdenum center by means of oxygen-atom transfer (OAT) reactions from the known MoVI starting material, TpiPr MoO2 Cl. The synthesized complexes were characterized by standard analytical methods and where possible by X-ray diffraction analysis. The aqueous stability of the compounds was studied by means of UV/Vis spectroscopy and the impact of the attached ligand scaffolds on the oxidation potentials (MoIV to MoV ) was studied by cyclic voltammetry. Utilizing polyvinylpyrrolidone (PVP) as a solubilizing agent, adequate aqueous solubility for biological tests was obtained. Anticancer activity tests and preliminary mode of action studies have been performed in vitro and in vivo.

Predicting the influence of a p2-symmetric substrate on molecular self-organization with an interaction-site model.

An interaction-site model can a priori predict molecular self-organisation on a new substrate in Monte Carlo simulations. This is experimentally confirmed with scanning tunnelling microscopy on Fréchet dendrons of a pentacontane template. Local and global ordering motifs, inclusion molecules and a rotated unit cell are correctly predicted.

Synthesis and characterization of TpiPrMoO(S2PR2) (R = Pri, Ph, OEt, OPri, (-)-mentholate) and {HB(OMe)(Pripz)2}MoO(S2PPri2), including isomers of known 1,2-borotropically-shifted complexes.

Green/blue TpiPrMoO(S2PR2) (TpiPr = hydrotris(3-isopropylpyrazolyl)borate; R = Pri, Ph, OEt, OPri, (-)-mentholate) complexes were synthesized and characterized by elemental analysis, mass spectrometry, IR and NMR spectroscopy, and X-ray crystallography. The diamagnetic, six-coordinate, oxo-Mo(IV) complexes possess distorted octahedral geometries defined by terminal oxo, bidentate dithio acid, and tridentate TpiPr ligands. The R = Pri and Ph derivatives are isomers of previously reported 1,2-borotropically shifted complexes, TpiPr*MoO(S2PR2) (TpiPr* = hydrobis(3-isopropylpyrazolyl)(5-isopropylpyrazolyl)borate; ref: Inorg. Chem. 1996, 35, 5368). Conversion of TpiPrMoO(S2PPh2) into TpiPr*MoO(S2PPh2) at elevated temperatures (>80 degrees C) showed that the borotropically shifted isomer was thermodynamically more stable than the unshifted species. Reaction with methanol converts TpiPrMoO(S2PPri2) into {HB(OMe)(Pripz)2}MoO(S2PPri2) (Pripz = 3-isopropylpyrazolyl), which was characterized by spectroscopic and crystallographic methods.

Pi-acid/pi-base carbonyloxomolybdenum(IV) complexes and their oxomolybdenum(VI/IV) precursors.

Brown TpiPrMoO(SR)(CO) (TpiPr = hydrotris(3-isopropylpyrazol-1-yl)borate; R = Et, iPr, Ph, p-tol, Bz) are formed when TpiPrMoO(SR)(NCMe) react with CO gas in toluene. The carbonyloxomolybdenum(IV) complexes exhibit nu(CO) and nu(Mo=O) IR bands at ca. 2025 and 935 cm(-1), respectively, and NMR spectra indicative of C(1) symmetry, with delta(C)(CO) ca. 250. The crystal structure of TpiPrMoO(SiPr)(CO), the first for a mononuclear carbonyloxomolybdenum complex, revealed a distorted octahedral geometry, with d(Mo=O) = 1.683(3) A, d(Mo-C) = 2.043(5) A, and angle(O=Mo-C) = 90.87(16) degrees . The blue-green acetonitrile precursors are generated by reacting cis-TpiPrMoO2(SR) with PPh3; they are unstable, display a single nu(Mo=O) IR band at ca. 950 cm(-1), and exhibit NMR spectra consistent with C1 symmetry. Red-brown cis-TpiPrMoO2(SR) (R = as above and tBu) are formed by metathesis of TpiPrMoO2Cl and HSR/NEt3 in dichloromethane. The complexes exhibit strong nu(MoO2) IR bands at ca. 925 and 895 cm(-1), and NMR spectra indicative of Cs symmetry; the isopropyl, p-tolyl, and benzyl derivatives possess distorted octahedral geometries, with d(Mo=O)(av) = 1.698 A and angle(MoO(2))(av) = 103.5 degrees.