Modifying the structure of dinuclear ruthenium complexes with antitumor activity

In order to modulate the structure of a recently developed series of antitumor-active, dinuclear Ru(II)–arene compounds, complexes 1c–4c were synthesized. The complexes were modified with respect to their pyridinone moieties and the spacer linking the two metal centers. More particularly, the series of dinuclear ruthenium(II) complexes was extended to compounds with longer spacers, i.e. tetradecane and 3,7,10-trioxotridecane, and the pyridinone ring was modified by replacing the methyl group by an ethyl group and by shifting the position of the methyl group. The organometallic ruthenium compounds were obtained from the reaction between [RuCl2(η6-p-isopropyltoluene)]2 and ligands 1b–4b with yields ranging from 41 to 67%. All compounds were characterized by standard methods: MS, 1H and 13C NMR spectroscopy and elemental analysis. Copyright © 2008 John Wiley & Sons, Ltd.

[1]  I. Bratsos,et al.  Ruthenium Anticancer Compounds: Challenges and Expectations , 2007 .

[2]  L. Juillerat-Jeanneret,et al.  Remarkable Anticancer Activity of Triruthenium-Arene Clusters Compared to Tetraruthenium-Arene Clusters , 2007 .

[3]  Andrew D. Phillips,et al.  Development of ruthenium antitumor drugs that overcome multidrug resistance mechanisms. , 2007, Journal of medicinal chemistry.

[4]  Anna F. A. Peacock,et al.  Osmium(II) and ruthenium(II) arene maltolato complexes: rapid hydrolysis and nucleobase binding. , 2007, Chemistry.

[5]  P. Dyson,et al.  Classical and Non‐Classical Ruthenium‐Based Anticancer Drugs: Towards Targeted Chemotherapy , 2006 .

[6]  R. Scopelliti,et al.  Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis. , 2006, Inorganic chemistry.

[7]  B. Keppler,et al.  Electrospray ionization mass spectrometric study on the coordination behavior of dacarbazine towards transition metal ions , 2006 .

[8]  C. Orvig,et al.  Metal complexes of maltol and close analogues in medicinal inorganic chemistry. , 2006, Chemical Society reviews.

[9]  M. Jakupec,et al.  From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). , 2006, Journal of inorganic biochemistry.

[10]  Christian G Hartinger,et al.  Interactions of antitumor metallodrugs with serum proteins: advances in characterization using modern analytical methodology. , 2006, Chemical reviews.

[11]  P. Dyson,et al.  Metal-based antitumour drugs in the post genomic era. , 2006, Dalton transactions.

[12]  M. Jakupec,et al.  Redox behavior of tumor-inhibiting ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. , 2006, Dalton transactions.

[13]  I. Tavernelli,et al.  Influence of Hydrogen-Bonding Substituents on the Cytotoxicity of RAPTA Compounds , 2006 .

[14]  Katherine H Thompson,et al.  Metal complexes in medicinal chemistry: new vistas and challenges in drug design. , 2006, Dalton transactions.

[15]  Anna F. A. Peacock,et al.  Tuning the reactivity of osmium(II) and ruthenium(II) arene complexes under physiological conditions. , 2006, Journal of the American Chemical Society.

[16]  P. Sadler,et al.  Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes. , 2005, Chemical communications.

[17]  G. Stingeder,et al.  Two dimensional separation schemes for investigation of the interaction of an anticancer ruthenium(III) compound with plasma proteins , 2005 .

[18]  P. Dyson,et al.  In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes. , 2005, Journal of medicinal chemistry.

[19]  M. Galanski,et al.  1,1'‐Bis(oxazolin‐2‐yl)ferrocenes: An Investigation of Their Complexation Behavior toward [Pd(η3‐allyl)Cl]2 , 2005 .

[20]  U. Jaehde,et al.  Analysis of Platinum Adducts with DNA Nucleotides and Nucleosides by Capillary Electrophoresis Coupled to ESI‐MS: Indications of Guanosine 5′‐Monophosphate O6–N7 Chelation , 2004, Chembiochem : a European journal of chemical biology.

[21]  M. Jakupec,et al.  Gallium in cancer treatment. , 2004, Current topics in medicinal chemistry.

[22]  A. Timerbaev,et al.  Platinum metallodrug‐protein binding studies by capillary electrophoresis‐inductively coupled plasma‐mass spectrometry: Characterization of interactions between Pt(II) complexes and human serum albumin , 2004, Electrophoresis.

[23]  B. Keppler,et al.  A comparative study of adduct formation between the anticancer ruthenium(III) compound HInd trans-[RuCl4(Ind)2] and serum proteins. , 2004, Journal of inorganic biochemistry.

[24]  J. Schellens,et al.  A Phase I and Pharmacological Study with Imidazolium-trans-DMSO-imidazole-tetrachlororuthenate, a Novel Ruthenium Anticancer Agent , 2004, Clinical Cancer Research.

[25]  Thomas J. Meyer,et al.  Comprehensive Coordination Chemistry II , 2004 .

[26]  G. Allmaier,et al.  Transferrin binding and transferrin-mediated cellular uptake of the ruthenium coordination compound KP1019, studied by means of AAS, ESI-MS and CD spectroscopy , 2004 .

[27]  M. Galanski,et al.  Synthesis, crystal structures, and electrospray ionisation mass spectrometry investigations of ether- and thioether-substituted ferrocenes , 2003 .

[28]  C. S. Allardyce,et al.  Synthesis and characterisation of some water soluble ruthenium(II)–arene complexes and an investigation of their antibiotic and antiviral properties , 2003 .

[29]  T. Uzbay,et al.  New analgesic and antiinflammatory agents 4(1H)-pyridinone derivatives. , 2002, European journal of medicinal chemistry.

[30]  L. Gano,et al.  Synthesis, chelating properties towards gallium and biological evaluation of two N-substituted 3-hydroxy-4-pyridinones. , 2000, Journal of inorganic biochemistry.

[31]  K. Severin,et al.  Halfsandwich complexes of ruthenium(II), rhodium(III) and iridium(III) with N-substituted 3-hydroxy-2-methyl-4-pyridone ligands , 1999 .

[32]  K. Polborn,et al.  Metallorganische Verbindungen mit N-substituierten 3-Hydroxy-2-methyl-4-pyridon-Liganden: quadratisch-planare Rhodium(I)-, Iridium(I)- und Palladium(II)-Komplexe , 1999 .

[33]  Ying Liang,et al.  Assembly of Mesoporous Lamellar Silicas with Hierarchical Particle Architectures , 1997 .

[34]  Rln Harris Potential wool growth inhibitors. Improved syntheses of mimosine and related 4(1H)-Pyridones , 1976 .

[35]  N. Farrell,et al.  Metal Complexes as Drugs and Chemotherapeutic Agents , 2003 .

[36]  C. S. Allardyce,et al.  [Ru(η6-p-cymene)Cl2(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo- [3.3.1.1]decane): a water soluble compound that exhibits pH dependent DNA binding providing selectivity for diseased cells , 2001 .

[37]  B. Noll,et al.  Chemistry and Pharmacokinetics of Gallium Maltolate, a Compound With High Oral Gallium Bioavailability , 2000, Metal-based drugs.