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.
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.
The stereoselective synthesis of a set of four stable 5-hydroxyeicosatetraenoic acid (HETE) 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 diastereoselective 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
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