title: Antitumor pentamethylcyclopentadienyl rhodium complexes of maltol and allomaltol: synthesis, solution speciation and bioactivity.
abstract: The reaction of the dimer [Rh(III)(pentamethylcyclopentadienyl)(μ-Cl)Cl]2 ([Rh(III)(Cp*)(μ-Cl)Cl]2) with the hydroxypyrone ligands maltol and allomaltol affords complexes of the general formula [Rh(III)(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, (1)H NMR spectroscopy and UV-visible spectrophotometry. Speciation was studied in the presence and in the absence of chloride ions. Hydrolysis of [Rh(III)(Cp*)(H2O)3](2+) gave dimeric mixed hydroxido species [(Rh(III)(Cp*))2(μ-OH)3](+) and [(Rh(III)(Cp*))2(μ-OH)2Z2] (Z=H2O/Cl(-)). Formation of the mononuclear complexes [Rh(III)(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 a chlorido/hydroxido co-ligand exchange resulted in the formation of the mixed-hydroxido species [Rh(III)(Cp*)(L)(OH)] in the basic pH range. Replacement of the chlorido by an aqua ligand in the complex [Rh(III)(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 Rh(III) complexes was compared to analogous [Ru(II)(η(6)-p-cymene)] species and higher conditional stabilities were found in the case of the Rh(III) compounds at pH7.4.
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Dömötör
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Aicher
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Schmidlehner
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Novak
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roller
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; University of Vienna, Research Platform Translational Cancer Therapy Research, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; University of Vienna, Research Platform Translational Cancer Therapy Research, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kandioller
authors.affiliation: School of Chemical Sciences, University of Auckland, PB: 92019, 1142 Auckland, New Zealand.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; University of Vienna, Research Platform Translational Cancer Therapy Research, Waehringer Str. 42, A-1090 Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address: enyedy@chem.u-szeged.hu.
authors.forename: Éva A
authors.initials: ÉA
authors.lastname: Enyedy
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D011753:Pyrones / Q000737:chemistry*; D012238:Rhodium / Q000737:chemistry*; D012428:Ruthenium / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D008024:Ligands; D011753:Pyrones; C550316:allomaltol; C008316:maltol; D012428:Ruthenium; D012238:Rhodium
keywords: Cytotoxicity; Equilibria; Hydroxypyrones; Rhodium(III); Stability constants; X-ray crystal structure