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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., (© SBIC 2012)

The cytostatic properties of novel rhodium(III) thiacrown ether complexes [RhCl(LL)([9]aneS(3))](n+) with either aromatic κ(2)N ligands (n = 2) or anionic chelate ligands (n = 1) have been investigated for the human cancer cell lines HT-29 and MCF-7 and for immortalized HEK-293 cells. Taken together with literature IC(50) values for analogous complexes with polypyridyl ligands or 1,4-dithiane, the in vitro assays indicate that dicationic complexes with soft κ(2)N (imino) or κ(2)S (thiaether) ligands exhibit significantly higher antiproliferative effects than those with hard κ(2)N (amino) ligands. Dicationic complexes are more active than monocationic complexes with similar ligands. Pronounced apoptosis-inducing properties towards Jurkat cells were established for complexes with LL = bpm, dpq, and 1,4-dithiane. The order of activity (bpm > 1,4-dithiane > dpq > bpy) contrasts to that observed for adhesive cancer cells (bpm > bpy, 1,4-dithiane > dpq). Necrosis is insignificant in all cases. The percentage of Jurkat cells exhibiting apoptosis after 24 or 48 h incubation periods is directly correlated to the percentage of cells exhibiting high levels of reactive oxygen species. As established by online monitoring with a sensor chip system, treatment of MCF-7 cells with the bpm and 1,4-dithiane complexes leads to a significant and permanent concentration-dependent decrease in oxygen consumption and cellular adhesion.

The antiproliferative properties and cellular impact of novel substitutionally inert rhodium(III) complexes of the types [Rh{(CH₃)₂ NCS₂}₂(pp)]Cl 3-5 (pp=5,6-Me₂phen, dpq, dppz) and OC-6-23-[Rh(2-S-py)₂(pp)]Cl 6 and 7 (2-S-py=pyridine-2-thiolate; pp=dpq, dppz) have been investigated for the adherent human cancer cell lines MCF-7 and HT-29 and for non-adherent Jurkat cells. Whereas CD and viscosity measurements indicate that the polypyridyl ligands of 4 and 5 intercalate into CT DNA, this is not the case for the analogous pyridine-2-thiolate complexes 6 and 7. Complexes 3-7 all exhibit a high antiproliferative activity towards MCF-7 and HT-29 cells, with IC(50) values in the range 0.055-0.285 μM. As established by online monitoring with a cell-based sensor chip, the highly cytostatic complex 6 (IC(50)=0.059 and 0.078 μM) invokes an immediate concentration-dependent reduction of MCF-7 cell respiration and a time-delayed decrease in cellular impedance, which can be ascribed to the induction of cell death. Annexin V/PI assays demonstrated that 6 also has a pronounced antiproliferative activity towards Jurkat cells and that it invokes extensive apoptosis and high concentrations of reactive oxygen species in these leukemia cells. The observation of a dose-dependent inhibition of the oxygen consumption of isolated mice mitochondria indicates the involvement of an intrinsic mitochondrial pathway in this process., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The antiproliferative properties and biological impact of octahedral iridium(III) complexes of the type fac-[IrCl3 (DMSO)(pp)] containing pp=phenanthroline (1) and its 4- and 5-methyl (2, 3) and 4,7- and 5,6-dimethyl derivatives (4, 5) were investigated for both adherent and non-adherent cells. A series of similar rhodium(III) complexes were studied for comparison purposes. The antiproliferative activity toward MCF-7 cancer cells increases eightfold from IC50=4.6 for 1 to IC50=0.60 μM for 5, and an even more pronounced 18-fold improvement was established for the analogous rhodium complexes 6 and 8, the respective IC50 values for which are 1.1 and 0.06 μM. Annexin V/propidium iodide assays demonstrated that the 5,6-dimethylphenanthroline complexes 5 and 8 both cause significant inhibition of Jurkat leukemia cell proliferation and invoke extensive apoptosis but negligible necrosis. The percentages of Jurkat cells exhibiting high levels of reactive oxygen species correlate with the percentages of cells undergoing apoptosis. The antiproliferative activity of 5 and 8 is strongly selective toward MCF-7 and HT-29 cancer cells over normal HFF-1 and immortalized HEK-293 cells. Complex 5 also exhibits high selectivity toward BJAB lymphoma cells relative to healthy leukocytes. Both 5 and 8 invoke permanent decreases in the adhesion and respiration of MCF-7 cells., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.

The Rh(III) polypyridyl complexes of the type [RhCl(pp)([9]aneS(3))](2+) [(pp)=2,2'-bipyridine (bpy), 2,2'-bipyrimidine (bpm),1,10-phenanthroline (phen), pyrazino[2,3-f]quinoxaline (tap), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq), dipyrido[2,3-a:2',3'-c]phenazine (dppz)] 2-7 have been prepared in a stepwise manner by treatment of RhCl(3).3H(2)O with the appropriate polypyridyl ligand (pp) followed by 1,4,7-trithiacyclononane. Interactions of the polypyridyl complexes with DNA were investigated by CD and UV/visible spectroscopy and by gel electrophoresis. The dpq complex 6 cleaves DNA exiguously in the dark, but UV irradiation is required to induce nuclease activity for the bpy complex 2. Whereas 2 [IC(50) values: 12.8 (+/-0.2) and 4.4 (+/-0.1)microM] exhibits significantly higher cytotoxicities towards MCF-7 and HT-29 cells than 4 [IC(50) values: 36.3 (+/-6.0) and 72.2 (+/-8.0)], the activity of complexes in the series 4/6/7 correlates directly with the size of the polypyridyl ligand, as documented by their respective IC(50) values of 72.2 (+/-8.0), 20.9 (+/-2.8) and 7.4 (+/-2.2) towards HT-29 cells. Complexes of the nitrogen-rich ligands bpm (3) [IC(50) values: 1.7 (+/-0.5) and 1.9 (+/-0.1)microM] and tap (5) [IC(50) values: 11.5 (+/-0.6) and 7.6 (+/-4.8)microM] are considerably more potent than their bpy and phen counterparts 2 and 4. Measurement of the lactate dehydrogenase release for lymphoma (BJAB) cells after 1h incubation demonstrates that unspecific necrosis is negligible for the most active compounds 3 and 7. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72h incubation and significant loss of the mitochondrial membrane potential in lymphoma cells indicates that the intrinsic pathway is involved.

Meridional rhodium(III) polypyridyl complexes of the type mer-[RhX(3)(DMSO)(pp)] (X=Cl, pp=phen 1, dpq 2, dppz 3; X=Br, pp=phen 4) represent a promising class of potent cytostatic agents for the treatment of lymphoma and leukemia. Exposure of their DMSO solutions to light leads to slow isomerization to mixtures of the mer and the generally less active fac isomers. As a result, the IC(50) values of 1 and 2 toward HT-29 cells increase from 0.19 and 0.069 microM on immediate use in the dark to 0.66 and 0.312 microM, respectively, after exposure of their DMSO stock solutions to light for 7 days. In striking contrast, the complexes mer-[IrX(3)(DMSO)(phen)] (X=Cl 7, Br 8) are significantly less cytotoxic than their facial Ir(III) polypyridyl counterparts: IC(50)=20.3 microM for 7 and 4.6 microM for fac-[IrCl(3)(DMSO)(phen)] 5 toward MCF-7 cells. The IC(50) values for the complexes fac-[IrX(3)(L)(pp)] 9-13 decrease in the orders: a) Cl>Br for X and b) H(2)O>DMSO for L. Specific apoptotic cell death by DNA fragmentation was detected for leukemia (NALM-6) and lymphoma (BJAB) cells after incubation with 2, 3, and 11 (X=Br, L=H(2)O, pp=phen) for 72 h. Loss of the mitochondrial membrane potential in lymphoma cells indicates that apoptosis is mediated via the intrinsic mitochondrial pathway. LDH release assays after 1 or 3 h demonstrate that necrotic damage is negligible.

The complexes mer-[RhCl 3(DMSO-kappa S)(pp)] 1a- 5a may be prepared by reaction of mer,cis-[RhCl 3(DMSO-kappa S) 2(DMSO-kappa O)] with the appropriate polypyridyl ligand (pp = bpy, phen, dpq, dppz, dppn) in CH 3OH/H 2O solution at 75 degrees C. The mer isomers of 1a- 5a are stable in chloroform solution but those of 1a and 2a isomerize rapidly to a mixture of fac and mer isomers in DMSO. The complexes are potent in vitro cytotoxic agents and exhibit IC 50 values that are strongly dependent on the size of the polypyridyl ligand. IC 50 values of, respectively, 4.0 (0.5) and 1.9 (0.5), 0.40 (0.06) and 0.19 (0.05), and 0.079 (0.012) and 0.069 (0.021) microM are observed for 1a- 3a against the human cell lines MCF-7 (breast cancer) and HT-29 (colon cancer). Cellular uptake studies showed a rapid and high accumulation of the polypyridyl compounds. Treatment of HT-29 and MCF-7 cells with 3a leads to significant decreases in cellular oxygen consumption and the rate of extracellular acidification.

Abstract: Until recently, Rh(III) and particularly Ir(III) complexes were generally considered as being unlikely candidates for anticancer agents owing to the typical kinetic inertness of their transition metal centres. Systematic studies on the cellular impact of a range of octahedral Rh(III) complexes containing polypyridyl and other aromatic chelates have now, however, demonstrated that high cytotoxicity in cancer cells and in certain cases promising relative tolerance by healthy cells can be achieved by judicious selection of the remaining ligands. Current knowledge on the biological properties of Rh(III) and Ir(III) compounds is reviewed in this article, with particular emphasis being placed on design strategies and on their solution behaviour, DNA binding preferences, structure–activity relationships and apoptosis induction in both adhesive and non-adhesive cells. [Copyright &y& Elsevier]

Abstract: Half-sandwich organorhodium(III) complexes of the type [(η5-C5Me5)RhCl(pp)] (CF3SO3) containing polypyridyl ligands (pp) represent a promising class of cytostatic agents. Replacement of the polypyridyl ligands of complexes 1 (pp=phen) and 6 (pp=dppz) by methyl-substituted derivatives in 2–5 (pp=4-Mephen, 5-Mephen, 4,7-Me2phen, 5,6-Me2phen) and 7 (pp=Me2dppz) leads to a significant improvement in their antiproliferative activity towards human MCF-7 and HT-29 cancer cells. For instance, the IC50 value towards HT-29 cells decreases from 4.3±0.2μM for 6 to 0.98±0.49μM for complex 7. In contrast, no activity (IC50 >100μM) was observed for the HOOC and n-BuNHCO substituted dppz complexes 8 and 9. UV/vis, CD and NMR spectra for mixtures of complexes 7–9 with CT DNA were in accordance with intercalation of the substituted dppz ligands between the base pairs of the double helix and direct evidence for this binding mode was also provided by a 2D NOESY study for complex 7 with the hexanucleotide d(5′-CGTCGG-3′). Each of the methyl-substituted phen complexes 2–5 is significantly more active towards immortalized HEK-293 cells (IC50 values 0.40±0.02 to 0.94±0.02μM) than towards the cancer cells. Flow cytometric measurements of DNA fragmentation in BJAB cells following an incubation period of 72h with 1, 5 and 6 indicate that the complexes induce specific apoptotic cell death in the non-adherent lymphoma cells. [Copyright &y& Elsevier]

Abstract: The DNA binding of polypyridyl (pp) (η5-C5Me5)RhIII complexes of the types [(η5-C5Me5)RhCl(pp)](CF3SO3) (2–6) (pp=bpy, phen, dpq, dppz, dppn), [(η5-C5Me5)Rh{(Me2N)2CS}(pp)](CF3SO3)2 (7–9) (pp=dpq, dppz, dppn) and [(η5-C5Me5)Rh(L)(pp)](CF3SO3) (10) (L=C6H5S−) and (11) (L=C10H7S−) has been studied by UV/Vis spectroscopy, circular dichroismus and viscosity measurements. Complexes 3–11 are cytotoxic towards the human MCF-7 breast and HT-29 colon cancer cell lines and exhibit IC50 values in the range 0.56–10.7μM. Stable intercalative binding into CT-DNA is indicated for the dpq and dppz complexes by large increases ΔT m of 6–12°C in the DNA thermal denaturation temperature for r =[complex]/[DNA]=0.1 and by induced CD bands and large viscosity increases. In contrast, significant DNA lengthening is not observed after incubation of the biopolymer with the dppn complexes 2 and 9 at molar ratios of r <0.08. Pronounced hypochromic shifts for the π–π∗ transitions of the dppn ligands in the range 320–425nm indicate the possible presence of surface stacking. The in vitro cytotoxicities of the chloro complexes 4–6 and the (Me2N)2CS complexes 7–9 are dependent on the size of the polypyridyl ligand with IC50 values decreasing in the order dpq>dppz>dppn. For instance, IC50 values of 5.3, 1.5 and 0.91μM were determined for 7–9 against MCF-7 cells. Rapid Cl−/H2O exchange leads the formation of aqua dications for 4–6, whose levels of cellular uptake and cytotoxicities are similar to those established for 7–9. Intramolecular interactions between the aromatic thiolate and dppz ligands of 10 and 11 prevent significant DNA intercalation. X-ray structural determinations have been performed for 2–7 and 11. [Copyright &y& Elsevier]