Am(m)ines Make the Difference: Organoruthenium Am(m)ine Complexes and Their Chemistry in Anticancer Drug Development

Abstract

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.

Half‐Sandwich Ruthenium(II) Biotin Conjugates as Biological Vectors to Cancer Cells

“…The geometrical parameters of the complex are in agreement with previously determined structures of compounds, which vary only in the nature of the N‐donor ligands 32. 33 The average RuC bond length in 6 is 2.186 Å, whereas RuCl1, RuCl2 and RuN distances are 2.4194(4), 2.4026(4), and 2.1368(12) Å, respectively (in comparison for [Ru(η 6 ‐ p ‐cymene)Cl 2 (NH 3 )], RuC av 2.170(8), RuCl1 2.4157(6), RuCl2 2.4157(6), and RuN 2.130(3) Å) 32. The crystal structure of 6 was employed as the starting point for subsequent docking studies.…”

“…The detection of complexes with coordinated monodentate N‐donor ligands can be challenging with ESI‐MS and indicates limited complex stability under the ESI spraying conditions 31. 32 However, this does not reflect the situation in solution. Interestingly, such ions were not observed for the complexes with aminohexanoic spacers (i.e., 8 and 11 ).…”

Ruthenium–Arene–β‐Carboline Complexes as Potent Inhibitors of Cyclin‐Dependent Kinase 1: Synthesis, Characterization and Anticancer Mechanism Studies

“…The higher cytotoxicities of complex 3 and 6 may also be related to their faster rate of hydrolysis. It has been reported that hydrolysis of the RuCl bond of Ru II –arene complexes are important for their activation, forming the aqua products that bind to DNA or protein 21b. 24…”

An Organoruthenium Anticancer Agent Shows Unexpected Target Selectivity For Plectin

“…Only RAPTA, which is an organoruthenium drug candidate with antimetastatic properties, [9] was assayed in as imilar setting Hydrolyzed ruthenium-arene metallodrugs face innumerous potential binding partners intracellularly.T arget profiling by affinity purification is suitable to profile for potential targets by immobilizing ad rug on solid support and exposing it to whole cell lysates.…”