Influence of structural variation on the anticancer activity of RAPTA-type complexes: ptn versus pta

A series of compounds of the general formula [M(eta6-arene)(ptn)Cl]X (M = Ru, Os; arene = p-cymene, benzene, toluene, hexamethylbenzene; ptn = 3,7-dimethyl-7-phospha-1,3,5-triazabicyclo[3.3.1]nonane; X = Cl-, BF4-) have been prepared and characterized spectroscopically. X-ray diffraction was additionally used to characterize four of the complexes in the solid state. The hydrolysis of the compounds was studied, and their cytotoxicity was evaluated in A2780 ovarian cancer cells and found to be comparable to that of known RAPTA complexes based on 7-phospha-1,3,5-triazatricyclo[3.3.1.1]decane (pta). The reactivity of the complexes toward double-stranded oligonucleotides and the model protein ubiquitin was investigated using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and gel electrophoresis, demonstrating a strong preference for the formation of covalent adducts with the protein. Correlations among compound structure, hydrolysis, biomolecular interactions, and cytotoxicity are established.