Cell‐Selective, Apoptosis‐inducing Rhodium(III) Crown Thiaether Complexes

Abstract

Half-sandwich rhodium(III) polypyridyl (pp) complexes with the metal atom capped by the facial crown thiaether 1,4,7-trithiacyclononane [9]aneS(3) represent a promising class of apoptosis-inducing potent cytostatic agents. The necrotic damage caused by the complexes is negligible. In vitro cytotoxicity assays with the human cancer cell lines MCF-7 and HT-29 and immortalized HEK-293 cells indicate that the dicationic kappa(2)N(imino) complexes [([9]aneS(3))RhCl(pp)](2+) are much more active than monocationic complexes [([9]aneS(3))RhCl(2)(L)](+) (L=imidazole, CH(3)CN). Whereas the kappa(2)N(amino) complex [([9]aneS(3))RhCl(piperazine)](2+) is inactive, replacing piperazine with the structurally analogous kappa(2)S (thiaether) ligand 1,4-dithiane restores cytotoxicity as evidenced by IC(50) values in the range 8.1-11.6 microM. Spectroscopic (CD, UV/Vis, NOESY) and viscosity measurements indicate that the active dppz complex 8 (IC(50) values: 4.7-8.9 microM) exhibits strong intercalative binding towards DNA whereas the even more potent bipyrimidine complex 9 (IC(50) values: 0.6-1.9 microM) causes no alteration of the duplex B conformation. Weaker intercalative binding is observed for the dpq complex 7. A comparative annexin V-propidium iodide binding assay with lymphoma (BJAB) cells and healthy leukocytes demonstrates that the cytotoxic activity of complex 8 and particularly complex 9 is highly selective towards the malignant cells.

Antileukemic activity and cellular effects of rhodium(III) crown thiaether complexes

“…6 in accordance to that employed for the previously published compounds [RhCl(LL) ([9] aneS 3 )] 2? 7-14 (LL = bpy, bpm = 2,2 0 -bipyrimidine, phen, tap = pyrazino[2,3-f]quinoxaline, dpq, dppz, pip = piperazine, 1,4-dithiane) (Bieda et al 2009a; (Bieda et al 2010) in analogy to the literature procedure for similar complexes with the dithiocarbamate ligands R 2 NCS 2 -(R = CH 3 CH 2 , PhCH 2 ) (Brandt and Sheldrick 1996). Complexes 1-6 were characterized by 1 H NMR and positive-ion LSIMS and gave satisfactory microanalyses.…”

“…Pronounced antiproliferative activity (IC 50 \ 12.8 lM) against MCF-7 and HT-29 cells has previously been established for ([9]aneS 3 )Rh III complexes containing the j 2 S ligand 1,4-dithiane (Bieda et al 2010) and the smallest pp ligand 2,2 0 -bipyridine (Bieda et al 2009a). We have now employed the anionic j 2 S ligand dmdtc -in ([RhCl(dmdtc)[9]aneS 3 )] ?…”

“…This trend is also followed by the IC 50 values for the ([9]aneS 3 )Rh III compounds towards HEK-293 cells. A different mechanism of action was postulated for compounds containing the nitrogen-rich bpm and tap ligands on the basis of their high antiproliferative activity (Bieda et al 2010). The results presented in Table 1 allow two structure-activity relationships to be established.…”

“…Elemental analyses were performed on a Vario EL of Elementar Analysensysteme GmbH. Compounds 7-14 were prepared in accordance with literature procedures (Bieda et al 2009a(Bieda et al , 2010.…”

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

“…complexes [5][6][7][8][9] and their Ir(III) analogues [7][8][9][10][11] containing polypyridyl and other chelating aromatic ligands were subsequently found to exhibit IC 50 values in the low micromolar range. Promising cell-deathinducing properties have also been established for Rh(III) complexes containing the facial j 3 S and j 3 N coligands 1,4,7-trithiacyclononane ( [9]aneS 3 ) [12,13] and tris(pyrazolyl)-methane (tpm) [14], as well as for the meridional trichlorido complexes mer-[RhCl 3 (DMSO)(pp)] (DMSO is dimethyl sulfoxide, pp is polypyridyl) [15,16].…”