Cellular impact and selectivity of half-sandwich organorhodium(III) anticancer complexes and their organoiridium(III) and trichloridorhodium(III) counterparts

Abstract

Half-sandwich organorhodium(III) complexes and their trichloridorhodium(III) counterparts are potent anticancer agents that enhance the formation of reactive oxygen species and invoke a strong induction of apoptosis in leukemia cells. The antiproliferative activity towards human MCF-7 and HT-29 adenocarcinoma cells of novel nonintercalating complexes containing the 5-substituted phenanthroline ligands 5,6-dimethylphenanthroline, 5-chlorophenanthroline, and 5-nitrophenanthroline (phen*) increases dramatically in the order [(η(5)-C(5)Me(5))IrCl(phen*)](CF(3)SO(3)) < [(η(5)-C(5)Me(5))RhCl(phen*)](CF(3)SO(3)) < mer-[RhCl(3)(DMSO)(phen*)] (DMSO is dimethyl sulfoxide). Improved activity was also achieved by attaching a cell-penetrating peptide to the dipyrido[3,2-a:2',3'-c]phenazine (dppz) ligand of an organorhodium(III) complex. Whereas 5-substitution led to significant improvements in the activity of the organoiridium(III) and trichloridorhodium(III) compounds in comparison with the parent phenanthroline complex, the IC(50) values of their organorhodium(III) counterparts remained effectively invariable. The high activities of the trichloridorhodium(III) complexes (IC(50) = 0.06-0.13 μM) were accompanied by pronounced selectivity towards human cancer cells in comparison with immortalized HEK-293 cells. In contrast, [(η(5)-C(5)Me(5))RhCl(5,6-Me(2)phen)](CF(3)SO(3)) (phen is phenanthroline) was markedly more active towards BJAB lymphoma cells than ex vivo healthy leukocytes and caused an immediate decrease in cellular adhesion possibly associated with interactions with membrane proteins. Its dppz analogue invoked an initial increase in glycolysis to compensate for reduced respiration before inducing a delayed onset of cell death. Strong antimitochondrial activity with respiration impairment and release of cytochrome c was established for both complexes.

Electronic Influences on the Stability and Kinetics of Cp* Rhodium(III) Azide Complexes in the iClick Reaction with Electron‐Poor Alkynes

“…[7] An extensive study of the anticancer activity of [RhCl(Cp*)(N^N)] + using N^N chelating ligands with an increasing aromatic surface area revealed low micromolar IC 50 values for MCF-7 human breast and HT-29 human colon cancer cells. [8,9] , and the reactions were accelerated by the presence of electron-donating groups at the 4,4′-position of the bpy coligand. These values are of a similar magnitude as those for the Staudinger ligation utilized for bio(macro)molecule functionalization.…”

Comparative solution equilibrium studies on pentamethylcyclopentadienyl rhodium complexes of 2,2ʹ-bipyridine and ethylenediamine and their interaction with human serum albumin

“…Whereas RhCp* complexes formed with 2-picolinic acid (pic) [12] and 3-hydroxy(thio)pyrones derivatized by morpholine, piperidine or N-methylpyrazine moieties [13] exhibited only poor or no bioactivity. Promising in vitro antiproliferative activities have been reported for the RhCp* complexes of (N,N) polypyridyl (pp) ligands by Sheldrick et al [14][15][16][17] possessing IC 50 values in the low micromolar range. However, the RhCp* complexes of the simplest bidentate alkylamino and aromatic N-donor ligands, namely ethylenediamine (en) and 2,2'-bipyridine (bpy) did not show significant cytotoxicity (IC 50 >100 μM measured in MCF-7 and HT-29 cells) [17].…”

Comparative equilibrium and structural studies of new pentamethylcyclopentadienyl rhodium complexes bearing (O,N) donor bidentate ligands

“…Recently more and more studies have focused on their antitumor activity [9,[11][12][13][14][15]. Among the first reports dealing with the anticancer properties of Rh(III) compounds were those investigating the salt reported by Sheldrick and co-workers [18][19][20][21]. Another very interesting concept involving dirhodium(II,II) complexes that preferentially bind to the nucleobases of RNA and DNA, thereby disrupting protein synthesis and cell proliferation, has been developed by Dunbar and co-workers [22][23][24].…”