Franz-Josef K. Rehmann

Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells

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.

Activity of [1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride against tumor colony-forming units

[1,2-di(cyclopentadienyl)-1,2-di(p-N,N-dimethylaminophenyl)-ethanediyl] titanium dichloride is a newly synthesized transition metal-based anti-cancer drug. We studied the anti-tumor activity of this drug (final concentrations: 25, 250 and 2500 μmol/l) against freshly explanted human tumors, using an in vitro soft agar cloning system. A total of eight tumor samples were evaluated using 1-h exposures. Additionally, the breast carcinoma cell line MCF-7 was examined with regard to sensitivity. The tested compound was markedly active against one renal cancer sample, whereas other renal tumors were resistant. Concentration-dependent anti-tumor activity was demonstrated for all samples except for melanoma. At concentrations of 250 μmol/l or less, the compound was less active than cisplatin or equally active at 0.2 μg/ml, whereas at 2500 μmol/l it showed a significant cytotoxic activity against a wide spectrum of tumor types. The highest activity was observed against renal carcinomas (three of three tumor specimens inhibited at 2500 μmol/l). Sensitivity was also highly remarkable in the breast cancer cell line MCF-7 inhibited in a range of 25–2500 μmol/l, whereas melanoma cells seemed to be profoundly resistant. Further clinical development of this drug appears warranted because of the broad cytotoxic activity shown.

Transition-metal-substituted phosphanes, arsanes and stibanes, LXIII.: Coupling reactions of alkynes with iron coordinated diphenylphosphane: generation of an alkenylphosphane and a chelating bisphosphane ligand1Part LXII. See [1].1

Abstract The reaction of {Cp(OC)2[H(Ph)2P]Fe}BF4 (1) with acetylenedicarboxylic acid dimethyl ester (2) in the presence of Et3N followed by addition of HBF4 leads to the cationic alkenylphosphane complex [Cp(OC)2Fe–P(Ph)2–C(CO2Me) C(CO2Me)H]BF4 (5). In contrast, the reaction of the bis(diphenylphosphane) complex {Cp(OC)[H(Ph)2P]2Fe}BF4 (6) with 2 yields {Cp(OC) Fe[P(Ph) 2 –C(H)(CO 2 Me)–C(H)(CO 2 Me)–P Ph2]}BF4 (7), bearing a functionalised dppe-analogous chelate phosphane. The molecular structures of 5 and 7 are determined by single crystal X-ray analysis.

Insertion of Diazoacetic Ester into the P–H Bond of the Cationic Primary and Secondary Phosphane-Substituted Iron Complexes [Cp(OC)2Fe–P(Ph)(R)H]+ (R = Ph, Me) and [(R′C5H4)(OC)2Fe–P(R)H2]+ [R = tBu, Ph, Mes; R′= H, Neomenthyl (NM)]

Treatment of the cationic secondary (phosphane)iron complexes [Cp(OC)2Fe–P(Ph)(R)H]BF4 (R = Ph, Me) (1a, b) with diazoacetic ester (2) yields the novel complex salts {Cp(OC)2Fe–P(Ph)(R)[N(H)–N=C(H)CO2Et]}BF4 (R = Ph, Me) (3a, b) by insertion of the terminal nitrogen atom of 2 into the P–H bond of 1a, b. Reaction of the primary (phosphane)iron complexes [(R′C5H4)(OC)2Fe–P(R)H2]BF4 [R = tBu, Ph, Mes; R′ = H, neomenthyl (NM)] (4a–e) with 2 affords the complex salts {(R′C5H4)(OC)2Fe–P(R)(H)[N(H)–N=C(H)CO2Et]}BF4 (5a–d) or {(R′C5H4)(OC)2Fe–P(R)[N(H)–N=C(H)CO2Et]2}BF4 (6a–d), depending on the molar ratio. The structures of 5c and 6b are proved by X-ray analysis.