Alkynyl gold(I) phosphane complexes: Evaluation of structure-activity-relationships for the phosphane ligands, effects on key signaling proteins and preliminary in-vivo studies with a nanoformulated complex.

Gold alkynyl complexes with phosphane ligands of the type (alkynyl)Au(I)(phosphane) represent a group of bioorganometallics, which has only recently been evaluated biologically in more detail. Structure-activity-relationship studies regarding the residues of the phosphane ligand (P(Ph)3, P(2-furyl)3, P(DAPTA)3, P(PTA)3, P(Et)3, P(Me)3) of complexes with an 4-ethynylanisole alkyne ligand revealed no strong differences concerning cytotoxicity. However, a relevant preference for the heteroatom free alkyl/aryl residues concerning inhibition of the target enzyme thioredoxin reductase was evident. Complex 1 with the triphenylphosphane ligand was selected for further studies, in which clear effects on cell morphology were monitored by time-lapse microscopy. Effects on cellular signaling were determined by ELISA microarrays and showed a significant induction of the phosphorylation of ERK1 (extracellular signal related kinase 1), ERK2 and HSP27 (heat shock protein 27) in HT-29 cells. Application of 1 in-vivo in a mouse xenograft model was found to be challenging due to the low solubility of the complex and required a formulation strategy based on a peanut oil nanoemulsion.

[1]  P. Dirac.  Quantum Mechanics of Many-Electron Systems , 1929 .

[2]  M. Arkin,et al.  A high throughput drug screen for Entamoeba histolytica identifies a new lead and target , 2012, Nature Medicine.

[3]  K. Rissanen,et al.  Luminescent alkynyl-gold(I) coumarin derivatives and their biological activity. , 2014, Dalton transactions.

[4]  R. Rubbiani,et al.  TrxR inhibition and antiproliferative activities of structurally diverse gold N-heterocyclic carbene complexes , 2013 .

[5]  A. Casini,et al.  Cytotoxic Gold(I) N‐heterocyclic Carbene Complexes with Phosphane Ligands as Potent Enzyme Inhibitors , 2014, ChemMedChem.

[6]  A. Casini,et al.  Antiproliferative Activity of Gold(I) Alkyne Complexes Containing Water-Soluble Phosphane Ligands , 2010 .

[7]  S. Berners‐Price,et al.  Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. , 2008, Journal of the American Chemical Society.

[8]  Stefan Wölfl,et al.  Microarray‐based kinetic colorimetric detection for quantitative multiplex protein phosphorylation analysis , 2011, Proteomics.

[9]  S. Wölfl,et al.  Detailed analysis of pro-apoptotic signaling and metabolic adaptation triggered by a N-heterocyclic carbene-gold(I) complex. , 2014, Metallomics : integrated biometal science.

[10]  S. Wölfl,et al.  Comparative in vitro evaluation of N-heterocyclic carbene gold(I) complexes of the benzimidazolylidene type. , 2011, Journal of medicinal chemistry.

[11]  C. Che,et al.  Chemical biology of anticancer gold(III) and gold(I) complexes. , 2015, Chemical Society reviews.

[12]  T. Muth,et al.  Auranofin and related heterometallic gold(I)-thiolates as potent inhibitors of methicillin-resistant Staphylococcus aureus bacterial strains. , 2014, Journal of inorganic biochemistry.

[13]  H. Lischka,et al.  PNO–CI (pair natural orbital configuration interaction) and CEPA–PNO (coupled electron pair approximation with pair natural orbitals) calculations of molecular systems. I. Outline of the method for closed‐shell states , 1975 .

[14]  S. Grimme,et al.  A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H-Pu. , 2010, The Journal of chemical physics.

[15]  Heike Bunjes,et al.  Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism. , 2013, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[16]  W. Berger,et al.  Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46 , 2014, Molecular Cancer Therapeutics.

[17]  A. Folda,et al.  Mitochondrial thioredoxin reductase inhibition by gold(I) compounds and concurrent stimulation of permeability transition and release of cytochrome c. , 2004, Biochemical pharmacology.

[18]  C. Che,et al.  A binuclear gold(I) complex with mixed bridging diphosphine and bis(N-heterocyclic carbene) ligands shows favorable thiol reactivity and inhibits tumor growth and angiogenesis in vivo. , 2014, Angewandte Chemie.

[19]  Frank Neese,et al.  The ORCA program system , 2012 .

[20]  I. Ott.  On the medicinal chemistry of gold complexes as anticancer drugs , 2009 .

[21]  F. Weigend,et al.  Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. , 2005, Physical chemistry chemical physics : PCCP.

[22]  Marco Häser,et al.  Auxiliary basis sets to approximate Coulomb potentials (Chem. Phys. Letters 240 (1995) 283-290) , 1995 .

[23]  P. Chiba,et al.  Synthesis and biological studies of some gold(I) complexes containing functionalised alkynes. , 2009, Dalton transactions.

[24]  G. Boscutti,et al.  Insights into the reactivity of gold-dithiocarbamato anticancer agents toward model biomolecules by using multinuclear NMR spectroscopy. , 2013, Chemistry.

[25]  A. Arcangeli,et al.  Design, synthesis and characterisation of new chimeric ruthenium(II)-gold(I) complexes as improved cytotoxic agents. , 2015, Dalton Transactions.

[26]  A. Klegeris,et al.  The biological activity of auranofin: implications for novel treatment of diseases , 2012, Inflammopharmacology.

[27]  J. C. Lima,et al.  Applications of gold(I) alkynyl systems: a growing field to explore. , 2011, Chemical Society reviews.

[28]  Wang,et al.  Generalized gradient approximation for the exchange-correlation hole of a many-electron system. , 1996, Physical review. B, Condensed matter.

[29]  W. Kean,et al.  Clinical pharmacology of gold , 2008, Inflammopharmacology.

[30]  Ruben Abagyan,et al.  A gold(III) porphyrin complex with antitumor properties targets the Wnt/beta-catenin pathway. , 2010, Cancer research.

[31]  J. Almlöf,et al.  Integral approximations for LCAO-SCF calculations , 1993 .

[32]  Stefan Wölfl,et al.  KOMA: ELISA-microarray calibration and data analysis based on kinetic signal amplification. , 2012, Journal of immunological methods.

[33]  J. C. Slater.  A Simplification of the Hartree-Fock Method , 1951 .

[34]  Burke,et al.  Generalized Gradient Approximation Made Simple. , 1996, Physical review letters.

[35]  A. Casini,et al.  Gold(I) NHC-based homo- and heterobimetallic complexes: synthesis, characterization and evaluation as potential anticancer agents , 2015, JBIC Journal of Biological Inorganic Chemistry.

[36]  M. Ginanneschi,et al.  Insights on the mechanism of thioredoxin reductase inhibition by gold N-heterocyclic carbene compounds using the synthetic linear selenocysteine containing C-terminal peptide hTrxR(488-499): an ESI-MS investigation. , 2014, Journal of inorganic biochemistry.

[37]  S. Wölfl,et al.  A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells , 2014, Molecular Cancer.

[38]  P. Leedman,et al.  A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer therapeutics targeted to mitochondria. , 2007, Biochemical pharmacology.

[39]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[40]  J. Ramos,et al.  Organometallic Titanocene–Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties , 2014, Organometallics.

[41]  Ismael Gracia,et al.  Luminescent di- and polynuclear organometallic gold(I)-metal (Au2, {Au2Ag}n and {Au2Cu}n) compounds containing bidentate phosphanes as active antimicrobial agents. , 2012, Chemistry.

[42]  V. Yam,et al.  Synthesis, photophysics and photochemistry of alkynylgold(I) phosphine complexes , 1996 .

[43]  D. Lloyd,et al.  Alkynyl-naphthalimide Fluorophores: Gold Coordination Chemistry and Cellular Imaging Applications. , 2015, Inorganic chemistry.

[44]  A. Casini,et al.  A golden future in medicinal inorganic chemistry: the promise of anticancer gold organometallic compounds. , 2014, Dalton transactions.

[45]  Laura Rodríguez,et al.  Phosphine-bridged dinuclear gold(I) alkynyl complexes: Thioredoxin reductase inhibition and cytotoxicity , 2013 .

[46]  F. Formaggio,et al.  Rational design of gold(III)-dithiocarbamato peptidomimetics for the targeted anticancer chemotherapy. , 2012, Journal of inorganic biochemistry.

[47]  F. Neese,et al.  Efficient and accurate local approximations to coupled-electron pair approaches: An attempt to revive the pair natural orbital method. , 2009, The Journal of chemical physics.

[48]  A. Casini,et al.  Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies , 2010, Medicinal research reviews.

[49]  A. Prokop,et al.  Gold(I) thiotetrazolates as thioredoxin reductase inhibitors and antiproliferative agents. , 2015, Dalton Transactions.

[50]  Catrin F. Williams,et al.  Gold(I) Complexes Derived from Alkynyloxy-Substituted Anthraquinones: Syntheses, Luminescence, Preliminary Cytotoxicity, and Cell Imaging Studies , 2012 .

[51]  S. Wölfl,et al.  On the biological properties of alkynyl phosphine gold(I) complexes. , 2012, Angewandte Chemie.

[52]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[53]  A. Casini,et al.  Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs , 2009 .