Synthesis, Structure, Protolytic Properties, Alkylating and Cytotoxic Activity of Novel Platinum(II) and Palladium(II) Complexes with Pyrazole-Derived Ligands

Novel platinum(II) and palladium(II) complexes [PtCl2(HL1)] (3a), [NH2(CH3)2][PtCl2(L1)] (3b), [PdCl2(HL1)] (4a), [NH2(CH3)2][PdCl2(L1)] (4b) and [PdCl(CH3CN)(L1)] (4c), where HL1 = 4-(2-hydroxybenzoyl)-2-(pyridin-2-yl)-1H-pyrazol-3-ol, have been synthesised as potential anticancer compounds. Protonation constants of the ligand were determined by pH-metric titration (log K1 = 7.74 ± 0.03; log K2 = 2.85 ± 0.05). The solid-state structures of complexes 3b and 4c have been determined by X-ray diffraction, showing square-planar coordination geometry of PtII and PdII ions. In addition, the compounds have been characterised by IR, 1H NMR and FAB mass spectrometry. The results of preliminary studies on the cytotoxic activity in vitro against HL-60 and NALM-6 leukaemia cell lines are also reported and the IC50 values compared with those of the metal-free ligand and cisplatin. Cytotoxic evaluation revealed that PtII and PdII complexes were active in the micromolar concentration range.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

[1]  Jinchao Zhang,et al.  Synthesis, cytotoxicity and DNA-binding levels of ammine/propylamine platinum(II) complexes with carboxylates. , 2007, European journal of medicinal chemistry.

[2]  Peter Mayer,et al.  Synthesis, cytotoxic effect, and structure-activity relationship of Pd(II) complexes with coumarin derivatives. , 2006, Inorganic chemistry.

[3]  C. Pettinari,et al.  Acylpyrazolone ligands : Synthesis, structures, metal coordination chemistry and applications , 2005 .

[4]  S. Patil,et al.  Synthesis, characterisation and biological evaluation of lanthanide(III) complexes with 3-acetylcoumarin-o-aminobenzoylhydrazone (ACAB). , 2005, Chemical & pharmaceutical bulletin.

[5]  I. Kostova,et al.  Cytotoxic activity of new lanthanum (III) complexes of bis-coumarins. , 2005, European journal of medicinal chemistry.

[6]  A. Szuławska,et al.  Biological evaluation of novel Pt(II) and Pd(II) complexes with pyrazole-containing ligands. , 2004, European journal of pharmacology.

[7]  K. Williams,et al.  Effect of amine ligand bulk on the interaction of methionine with platinum(II) diamine complexes. , 2004, Inorganic chemistry.

[8]  K. Erol,et al.  1‐N‐Substituted Thiocarbamoyl‐3‐phenyl‐5‐thienyl‐2‐pyrazolines: Synthesis and Evaluation as MAO Inhibitors , 2003, Archiv der Pharmazie.

[9]  M. Różalski,et al.  Cytotoxic effects, alkylating properties and molecular modelling of coumarin derivatives and their phosphonic analogues. , 2003, European journal of medicinal chemistry.

[10]  V. Brabec,et al.  DNA binding mode of the cis and trans geometries of new antitumor nonclassical platinum complexes containing piperidine, piperazine, or 4-picoline ligand in cell-free media. Relations to their activity in cancer cell lines. , 2003, Biochemistry.

[11]  Jan Reedijk,et al.  New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Y. Wan,et al.  Dimethylformamide as a carbon monoxide source in fast palladium-catalyzed aminocarbonylations of aryl bromides. , 2002, The Journal of organic chemistry.

[13]  P. Garnuszek,et al.  Biological investigation of the platinum(II)-[*I]iodohistamine complexes of potential synergistic anti-cancer activity. , 2002, Nuclear medicine and biology.

[14]  I. Kostova,et al.  Synthesis, Physicochemical Characterization, and Cytotoxic Screening of New Zirconium Complexes with Coumarin Derivatives , 2001, Archiv der Pharmazie.

[15]  B. S. Holla,et al.  Studies on arylfuran derivatives , 2000 .

[16]  T. Netzeva,et al.  Cytotoxic Activity of Cerium Complexes with Coumarin Derivatives. Molecular Modeling of the Ligands , 2000, Archiv der Pharmazie.

[17]  C. Giandomenico,et al.  Current status of platinum-based antitumor drugs. , 1999, Chemical reviews.

[18]  S. Lippard,et al.  Structure, Recognition, and Processing of Cisplatin-DNA Adducts. , 1999, Chemical reviews.

[19]  J. Reedijk.  Medicinal applications of heavy-metal compound , 1999 .

[20]  S. Rajski,et al.  DNA Cross-Linking Agents as Antitumor Drugs. , 1998, Chemical reviews.

[21]  L. Rashan,et al.  Synthesis and cytotoxic evaluation of the first trans-palladium(II) complex with naturally occurring alkaloid harmine , 1998 .

[22]  R. Fawzi,et al.  Chemical properties and cytotoxic activity of complexes of platinum(II) and palladium(II) containing dmso and various anions; synthesis and structural characterization of [Pt(dmso)2{O2(CO)2CCH2CH2CH2}] , 1998 .

[23]  R. Bhikhabhai,et al.  A Non-Radioactive Microtitre Plate Reverse Transcriptase (RT) Assay, Based on Immobilized Template, for Screening of RT Activity Inhibitors and Evaluation of their Mode of Action , 1997 .

[24]  E. De Clercq,et al.  Palladium(II) complexes of dialkyl alpha-Anilinobenzylphosphonates. Synthesis, characterization, and cytostatic activity. , 1996, Journal of inorganic biochemistry.

[25]  Ryszard Radomski,et al.  Microcomputer-controlled Electrochemical Universal Meter , 1995, Comput. Chem..

[26]  S. Fricker,et al.  Synthesis and cytotoxicity of some cyclometallated palladium complexes. , 1993, Journal of inorganic biochemistry.

[27]  J. Barrett,et al.  DNA gyrase inhibitory and antibacterial activity of some flavones (1) , 1993 .

[28]  G. Patnaik,et al.  Spasmolytic activity of angelicin: a coumarin from Heracleum thomsoni. , 1987, Planta medica.

[29]  D. Lydall,et al.  Mechanism of cytotoxicity of anticancer platinum drugs: evidence that cis-diamminedichloroplatinum(II) and cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) differ only in the kinetics of their interaction with DNA. , 1986, Cancer research.

[30]  A. Martell,et al.  Program PKAS: a novel algorithm for the computation of successive protonation constants , 1982 .

[31]  G. Coppola,et al.  An Improved Synthesis of 2-Methylchromone-3-carboxylic Acid and Its Esters , 1981 .

[32]  J. Shavel,et al.  Base rearrangement of chromone-3-carboxylic esters to 3-acyl-4-hydroxycoumarins , 1974 .

[33]  S. Kirschner,et al.  Anticancer and potential antiviral activity of complex inorganic compounds. , 1966, Journal of medicinal chemistry.

[34]  I. Kostova.  Gold coordination complexes as anticancer agents. , 2006, Anti-cancer agents in medicinal chemistry.

[35]  M. Jakupec,et al.  Tumour-inhibiting platinum complexes--state of the art and future perspectives. , 2003, Reviews of physiology, biochemistry and pharmacology.

[36]  D. Erol,et al.  Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines. , 2001, European journal of medicinal chemistry.

[37]  G. Mazur,et al.  Comparison of pharmacological and clinical activity between cisplatin and carboplatin in the treatment of solid tumours , 2000 .

[38]  K. Kawakami,et al.  Syntheses, antitumor activity, and molecular mechanics studies of cis-PtCl2(pzH)2 (pzH=pyrazole) and related complexes. Crystal structure of a novel Magnus-type double-salt [Pt(pzH)4][PtCl4][cis-PtCl2(pzH)2]2 involving two perpendicularly aligned 1D chains , 2000 .

[39]  I. Kostova,et al.  Synthesis, physicochemical characterisation and cytotoxic screening of new complexes of cerium, lanthanum and neodymium with Warfarin and Coumachlor sodium salts , 1999 .

[40]  Z. Otwinowski,et al.  [20] Processing of X-ray diffraction data collected in oscillation mode. , 1997, Methods in enzymology.

[41]  L. Rashan,et al.  Synthesis and characterization of novel biologically active platinum(II) and palladium(II) complexes of some β-carboline alkaloids , 1990 .

[42]  J. Beltrán,et al.  Miniglass, an interactive program for the evaluation of stability constants of metal/ligand complexes from potentiometric data , 1986 .

[43]  G. Zon.  4 Cyclophosphamide Analogues , 1982 .

[44]  M. Pétraud,et al.  Nouveau mode de cyclisation de céto-ylures.Application `a une synthèse originale d'acyl-3 hydroxy-4-coumarines et de l'hydroxy-11 benzo-(b) 12[h] xanthone-12 , 1981 .

[45]  G. P. Ellis,et al.  Benzopyrones. 9. Synthesis and pharmacology of some novel bischromones. , 1973, Journal of medicinal chemistry.

[46]  H. Gershon,et al.  PYRIMIDINES. III. SOME 6-SUBSTITUTED DI- AND TRICHLOROPYRIMIDINES. , 1963, Journal of medicinal chemistry.