7 research outputs found
Antitumor Pentamethylcyclopentadienyl Rhodium Complexes of Maltol and Allomaltol: Synthesis, Solution Speciation and Bioactivity
The reaction of the dimer [RhIII(pentamethylcyclopentadienyl)(m-Cl)Cl]2 ([RhIII(Cp*)(m-
Cl)Cl]2) with the hydroxypyrone ligands maltol and allomaltol affords complexes of the
general formula [RhIII(Cp*)(L)Cl] under standard and microwave conditions. The
organometallic compounds were characterized by standard analytical methods and in the case
of the allomaltol derivative in the solid state by single-crystal X-ray diffraction analysis. The
complexes showed similar cytotoxicity profiles and were proved to be moderately active
against various human cancer cell lines. The stoichiometry and stability of these complexes
were determined in aqueous solution by pH-potentiometry, 1H NMR spectroscopy and UVvisible
spectrophotometry. Speciation was studied in the presence and in the absence of
chloride ions. Hydrolysis of [RhIII(Cp*)(H2O)3]2+ gave dimeric mixed hydroxido species
[(RhIII(Cp*))2(m-OH)3]+ and [(RhIII(Cp*))2(m-OH)2Z2] (Z = H2O/Cl‒). Formation of the
mononuclear complexes [RhIII(Cp*)(L)Z] of maltol and allomaltol with similar and moderate
stability was found. These species predominate at physiological pH and decompose only
partially at micromolar concentrations. In addition, hydrolysis of the aqua complex or the
chlorido/hydroxido co-ligand exchange resulted in the formation of the mixed-hydroxido
species [RhIII(Cp*)(L)(OH)] in the basic pH range. Replacement of the chlorido by an aqua
ligand in the complex [RhIII(Cp*)(L)Cl] was monitored and with the help of the equilibrium
constants the extent of aquation at various chloride concentrations of the extra- and
intracellular milieu can be predicted. Complexation of these RhIII complexes was compared to
analogous [RuII(h6-p-cymene)] species and higher conditional stabilities were found in the
case of the RhIII compounds at pH 7.4
Contrasting anticancer activity of half-sandwich iridium(III) complexes bearing functionally diverse 2-phenylpyridine ligands
We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η5-Cp*)Ir(2-(R′-phenyl)-R-pyridine)Cl] bearing either an electron-donating (−OH, −CH2OH, −CH3) or electron-withdrawing (−F, −CHO, −NO2) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η5-Cp*)Ir(2-(2′-fluorophenyl)pyridine)Cl] (1) and [(η5-Cp*)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) exhibit the expected “piano-stool” configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD+. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC50 values ranging from 1 to 89 μM, with the most potent complex, [(η5-Cp*)Ir(2-(2′-methylphenyl)pyridine)Cl] (13) (A2780 IC50 = 1.18 μM), being 10× more active than the parent, [(η5-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η5-CpxPh)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η5-Cp*)Ir(2-(4′-fluorophenyl)pyridine)Cl] (2) and [(η5-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] (4) preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems