Synthesis, characterization and antitumor activity of 1,2-disubstituted ferrocenes and cyclodextrin inclusion complexes

Seven different ferrocene derivatives have been tested in vitro against Ehrlich ascites tumor cells. Neither ferrocene nor the monosubstituted derivative N,N-dimethylaminomethylferrocene showed cytotoxic activity (IC50 > 1000 μM for 3 h treatments). Better results were obtained with 1,2-disubstituted derivatives. The IC50 values ranged from 376.6 μM for 1,2-diformylferrocene to 71.2 μM for racemic 2-(N,N-dimethylaminomethyl)ferrocenecarboxamide. The latter derivative was also encapsulated in native β-cyclodextrin (CD), heptakis-2,3,6-tri-O-methyl-β-CD (TRIMEB) and 2-hydroxypropyl-β-CD (HPβCD) to give 1:1 (host:guest) inclusion compounds. The existence of true inclusion complexes in the solid state was confirmed by a combination of powder X-ray diffraction, thermogravimetric analysis, FTIR and 13C CP MAS NMR spectroscopy. The IC50 value for the β-CD inclusion compound was identical to that obtained for the nonincluded ferrocene derivative. By contrast, the inclusion compounds comprising TRIMEB and HPβCD yielded IC50 values of 25.2 and 20.0 μM, respectively. No obvious relationship could be established between the redox behavior of the compounds determined by cyclic voltammetry and the biochemical data.

The cytotoxic activity of several 1,2-disubstituted ferrocene derivatives tested in vitro against Ehrlich ascites tumor cells was found to vary from IC50 > 1000 μM for 1,2-bis(hydroxymethyl)ferrocene to IC50 71.2 μM for 2-(N,N-dimethylaminomethyl)ferrocenecarboxamide. An inclusion compound comprising the latter derivative and 2-hydroxypropyl-β-cyclodextrin exhibited an improved IC50 value of 20.0 μM.Figure optionsDownload as PowerPoint slide