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 [(η5-C5Me5)IrCl(phen*)](CF3SO3) < [(η5-C5Me5)RhCl(phen*)](CF3SO3) < mer-[RhCl3(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 IC50 values of their organorhodium(III) counterparts remained effectively invariable. The high activities of the trichloridorhodium(III) complexes (IC50 = 0.06–0.13 μM) were accompanied by pronounced selectivity towards human cancer cells in comparison with immortalized HEK-293 cells. In contrast, [(η5-C5Me5)RhCl(5,6-Me2phen)](CF3SO3) (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.

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 mm 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 mm. Annexin V/propidium iodide assays demonstrated that the 5,6-dimethylphenanthro-line 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.

The stereoselective synthesis of a set of four stable 5-hydroxyeicosatetraenoic acid (METE) analogues with a ferrocene backbone is described. The common substructure of all HETEs, the (2E,4Z)-1-hydroxyhexadiene moiety, was formally replaced by a ferrocenylmethanol fragment. Whereas the hydrophilic side chain remained the same as that of 5-HETE (butyrate), the lipophilic side chain was simplified by replacing the "natural" (Z,Z)-1,4-decadiene side chain with (Z)-1-heptene, 1-heptyne, 1-octyne, or phenylacetylene. As a key building block, Kagan's chiral acetal (derived from ferrocenecarbaldehyde) was used for the stereoselective generation of the planar-chiral substructure through diastereo-selective ortho-lithiation and subsequent formylation, methoxycarbonylation or iodination, respectively. The lipophilic side chain was installed either by a "salt-free" Wittig reaction or (better) by Pd-catalyzed Sonogashira coupling. The (Z)-selective semi-reduction of a (hindered) triple bond was achieved with NaBH4, PdI2 and PEG200. The introduction of the hydrophilic side chain was found to proceed with complete diastereoselectivity through addition of a titanium zinc organyl [prepared from ethyl 4-iodobutyrate, activated Zn powder and Ti(OiPr)(3)Cl] as a butyrate D-4 synthon to an aldehyde function using 2-methyltetrahydrofuran (2-Me-THF) as a solvent. The expected (R-p,5S) configuration of the products was confirmed by X-ray crystallography of an intermediate and by chemical correlation and NMR spectroscopy of a Mosher-type derivative. Preliminary biological experiments revealed that compound 4 [with a (Z)-heptenyl side chain] displayed significant apoptosis induction, whereas analogues with an alkynyl side chain were inactive. None of the METE analogues prepared showed significant inhibition of lipoxygenase (15-LOX) or cyclooxygenase (COX-2).

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.