title: 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.
abstract: 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.
authors: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany; PVZ - Center of Pharmaceutical Engineering, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany.
authors: Vincent
authors: V
authors: Andermark
authors: PVZ - Center of Pharmaceutical Engineering, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany; Institute of Pharmaceutical Technology, Technische Universität Braunschweig, Mendelssohnstrasse 1, 38106 Braunschweig, Germany.
authors: Katrin
authors: K
authors: Göke
authors: Gilead Sciences & IOCB Research Center, Department of Computational Chemistry, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague 6, Czech Republic; Department of Physical Chemistry, Palacky University, 77146 Olomouc, Czech Republic.
authors: Malte
authors: M
authors: Kokoschka
authors: Department of Biology, Institut für Pharmazie und Molekulare Biotechnologie, Ruperto-Carola University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors: Mohamed A
authors: MA
authors: Abu El Maaty
authors: State Key Laboratory of Synthetic Chemistry, Chemical Biology Center, The University of Hong Kong, 8/F, The Hong Kong Jockey Club Building for Interdisciplinary Research, 5, Sassoon Road, Pokfulam, Hong Kong; Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors: Ching Tung
authors: CT
authors: Lum
authors: State Key Laboratory of Synthetic Chemistry, Chemical Biology Center, The University of Hong Kong, 8/F, The Hong Kong Jockey Club Building for Interdisciplinary Research, 5, Sassoon Road, Pokfulam, Hong Kong; Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors: Taotao
authors: T
authors: Zou
authors: State Key Laboratory of Synthetic Chemistry, Chemical Biology Center, The University of Hong Kong, 8/F, The Hong Kong Jockey Club Building for Interdisciplinary Research, 5, Sassoon Road, Pokfulam, Hong Kong; Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors: Raymond Wai-Yin
authors: RW
authors: Sun
authors: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors: Elisabet
authors: E
authors: Aguiló
authors: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany; PVZ - Center of Pharmaceutical Engineering, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany.
authors: Luciano
authors: L
authors: Oehninger
authors: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors: Laura
authors: L
authors: Rodríguez
authors: PVZ - Center of Pharmaceutical Engineering, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany; Institute of Pharmaceutical Technology, Technische Universität Braunschweig, Mendelssohnstrasse 1, 38106 Braunschweig, Germany.
authors: Heike
authors: H
authors: Bunjes
authors: Department of Biology, Institut für Pharmazie und Molekulare Biotechnologie, Ruperto-Carola University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Wölfl
authors: State Key Laboratory of Synthetic Chemistry, Chemical Biology Center, The University of Hong Kong, 8/F, The Hong Kong Jockey Club Building for Interdisciplinary Research, 5, Sassoon Road, Pokfulam, Hong Kong; Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong.
authors: Chi-Ming
authors: CM
authors: Che
authors: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany; PVZ - Center of Pharmaceutical Engineering, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany. Electronic address: ingo.ott@tu-bs.de.
authors: Ingo
authors: I
authors: Ott
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002414:Cations, Monovalent; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D006046:Gold / Q000737:chemistry*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D006360:Heat-Shock Proteins; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones; D050607:Organogold Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D010720:Phosphines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000840:Anisoles; D000970:Antineoplastic Agents; D002414:Cations, Monovalent; D056831:Coordination Complexes; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D008024:Ligands; D018832:Molecular Chaperones; D050607:Organogold Compounds; D010720:Phosphines; D006046:Gold; D013880:Thioredoxin-Disulfide Reductase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C044646:phosphine
keywords: Alkyne; Cancer; Formulation; Gold; Microarray; Xenograft