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Am(m)ines Make the Difference: Organoruthenium Am(m)ine Complexes and Their Chemistry in Anticancer Drug Development
Author(s) -
Babak Maria V.,
Meier Samuel M.,
Legin Anton A.,
Adib Razavi Mahsa S.,
Roller Alexander,
Jakupec Michael A.,
Keppler Bernhard K.,
Hartinger Christian G.
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201202657
Subject(s) - chemistry , lipophilicity , reactivity (psychology) , ethylenediamine , aquation , adduct , ligand (biochemistry) , biphenyl , stereochemistry , combinatorial chemistry , hydrolysis , medicinal chemistry , biochemistry , kinetics , organic chemistry , receptor , pathology , medicine , physics , alternative medicine , quantum mechanics , reaction rate constant
With the aim of systematically studying fundamental structure–activity relationships as a basis for the development of Ru II arene complexes (arene= p ‐cymene or biphenyl) bearing mono‐, bi‐, or tridentate am(m)ine ligands as anticancer agents, a series of ammine, ethylenediamine, and diethylenetriamine complexes were prepared by different synthetic routes. Especially the synthesis of mono‐, di‐, and triammine complexes was found to be highly dependent on the reaction conditions, such as stoichiometry, temperature, and time. Hydrolysis and protein‐binding studies were performed to determine the reactivity of the compounds, and only those containing chlorido ligands undergo aquation or form protein adducts. These properties correlate well with in vitro tumor‐inhibiting potency of the compounds. The complexes were found to be active in anticancer assays when meeting the following criteria: stability in aqueous solution and low rates of hydrolysis and binding to proteins. Therefore, the complexes least reactive to proteins were found to be the most cytotoxic in cancer cells. In general, complexes with biphenyl as arene ligand inhibited the growth of tumor cells more effectively than the cymene analogues, consistent with the increase in lipophilicity. This study highlights the importance of finding a proper balance between reactivity and stability in the development of organometallic anticancer agents.