titanocene and Prostatic-Neoplasms

A series of tri- and bimetallic titanium-gold, titanium-palladium, and titanium-platinum derivatives of the general formulas [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)(AuCl)}(2)]·2THF [n = 0 (1); n = 2 (2); n = 3 (3)] and [TiCl(2){η(5)-C(5)H(4)κ-(CH(2))(n)PPh(2)}(2)(MCl(2))]·2THF [M = Pd, n = 0 (4); n = 2 (5); n = 3 (6) ; M = Pt, n = 0 (7); n = 2 (8); n = 3 (9)] have been synthesized and characterized by different spectroscopic techniques and mass spectrometry. The molecular structures of compounds 1-9 have been investigated by means of density functional theory calculations. The calculated IR spectra of the optimized structures fit well with the experimental IR data obtained for 1-9. The stability of the heterometallic compounds in deuterated solvents [CDCl(3), dimethyl sulfoxide (DMSO)-d(6), and mixtures 50:50 DMSO-d(6)/D(2)O and 1:99 DMSO-d(6)/D(2)O at acidic and neutral pH] has been evaluated by (31)P and (1)H NMR spectroscopy showing a higher stability for these compounds than for Cp(2)TiCl(2) or precursors [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)}(2)]. The new compounds display a lower acidity (1-2 units) than Cp(2)TiCl(2). The decomposition products have been identified over time. Complexes 1-9 have been tested as potential anticancer agents, and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and DU-145 human prostate cancer cells. TiAu(2) and TiPd compounds were highly cytotoxic for these two cell lines. The interactions of the compounds with calf thymus DNA have been evaluated by thermal denaturation (1-9) and by circular dichroism (1, 3, 4, and 7) spectroscopic methods. All of these complexes show a stronger interaction with DNA than that displayed by Cp(2)TiCl(2) at neutral pH. The data are consistent with electrostatic interactions with DNA for TiAu(2) compounds and for a covalent binding mode for TiM (M = Pd, Pt) complexes.

Topics: Animals; Antineoplastic Agents; Cattle; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Circular Dichroism; DNA; Female; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Nucleic Acid Conformation; Organometallic Compounds; Palladium; Phosphines; Platinum; Prostatic Neoplasms; Spectrophotometry, Infrared; Structure-Activity Relationship; Titanium; Uterine Cervical Neoplasms

Titanocene difluorides can be obtained by halide metathesis of the respective titanocene dichlorides with trimethyltin fluoride (Me(3)SnF), giving access to a new class of cytotoxic active substances. Furthermore, an improved method for the synthesis of diaryl-substituted titanocene dichlorides is presented.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Inhibitory Concentration 50; Kidney Neoplasms; LLC-PK1 Cells; Male; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Organometallic Compounds; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Swine

Advanced prostate cancer is not curable by current treatment strategies indicating a significant need for new chemotherapeutic options. Highly substituted ansa-titanocene compounds have shown promising cytotoxic activity in a range of cancers. The objectives of this study are to examine the effects of these titanocene compounds on prostate cancer cells. Prostate cell lines were treated with three novel titanocene compounds and compared to titanocene dichloride and cisplatin. Percent apoptosis, viability and cell cycle were assessed using propidium iodide DNA incorporation with flow cytometry. Cytochrome C was assessed by western blotting of mitochondrial and cytoplasmic fractions. Apoptosis Inducing Factor was assessed by confocal microscopy. These novel compounds induced more apoptosis compared to cisplatin in a dose dependent manner. Compound Y had the most significant effect on cell cycle and apoptosis. Despite the release of cytochrome C from the mitochondrial fraction there was no inhibition of apoptosis with the pan caspase inhibitor, ZVAD-FMK. AIF was shown to translocate from the cytosol to the nucleus mediating a caspase independent cell death. Bcl-2 over expressing PC-3 cells, which were resistant to cisplatin induced apoptosis, underwent apoptosis following treatment with all the titanocene compounds. This study demonstrates possible mechanisms by which these novel titanocene compounds can mediate their apoptotic effect in vitro. The fact that they can induce more apoptosis than cisplatin in advanced cancer cell lines would confer an advantage over cisplatin. They represent exciting new agents with future potential for the treatment of advanced prostate cancer.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Blotting, Western; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Cysteine Proteinase Inhibitors; Cytochromes c; Humans; Male; Molecular Structure; Organometallic Compounds; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Transfection