Benzimidazol-2-ylidene Gold(I) Complexes Are Thioredoxin Reductase Inhibitors with Multiple Antitumor Properties
- Riccardo Rubbiani
- ,
- Igor Kitanovic
- ,
- Hamed Alborzinia
- ,
- Suzan Can
- ,
- Ana Kitanovic
- ,
- Liliane A. Onambele
- ,
- Maria Stefanopoulou
- ,
- Yvonne Geldmacher
- ,
- William S. Sheldrick
- ,
- Gerhard Wolber
- ,
- Aram Prokop
- ,
- Stefan Wölfl
- , and
- Ingo Ott
Abstract

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands 1a−4a represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by 1a−4a in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex (2a) revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
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- Sina M. Hopff, Qifang Wang, Corazon Frias, Marie Ahrweiler, Nicola Wilke, Nathalie Wilke, Albrecht Berkessel, Aram Prokop. A metal-free salalen ligand with anti-tumor and synergistic activity in resistant leukemia and solid tumor cells via mitochondrial pathway. Journal of Cancer Research and Clinical Oncology 2021, 147 (9) , 2591-2607. https://doi.org/10.1007/s00432-021-03679-3
- Marcos A. S. Francisco, Felipe Fantuzzi, Thiago M. Cardozo, Pierre M. Esteves, Bernd Engels, Ricardo R. Oliveira. Taming the Antiferromagnetic Beast: Computational Design of Ultrashort Mn−Mn Bonds Stabilized by N‐Heterocyclic Carbenes. Chemistry – A European Journal 2021, 27 (47) , 12126-12136. https://doi.org/10.1002/chem.202101116
- Leiya Kou, Shuang Wei, Pei Kou. Current Progress and Perspectives on Using Gold Compounds for the Modulation of Tumor Cell Metabolism. Frontiers in Chemistry 2021, 9 https://doi.org/10.3389/fchem.2021.733463
- Nedaossadat Mirzadeh, Srinivasa Reddy Telukutla, Rodney Luwor, Steven Privér, Ganga Reddy Velma, Ranjith Kumar Jakku, Stephens Andrew N., Magdalena Plebanski, Hartinger Christian, Suresh Bhargava. Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism. Metallomics 2021, 13 (7) https://doi.org/10.1093/mtomcs/mfab039
- Hilke Burmeister, Pascal Dietze, Lutz Preu, Julia E. Bandow, Ingo Ott. Evaluation of Ruthenium(II) N-Heterocyclic Carbene Complexes as Antibacterial Agents and Inhibitors of Bacterial Thioredoxin Reductase. Molecules 2021, 26 (14) , 4282. https://doi.org/10.3390/molecules26144282
- Shipra Yadav. Potential of Metal Complexes for the Treatment of Cancer: Current Update and Future Prospective. 2021, 183-204. https://doi.org/10.1002/9781119640929.ch7
- Leticia B. Rosa, Rochanna L. Aires, Laiane S. Oliveira, Josielle V. Fontes, Danilo C. Miguel, Camilla Abbehausen. A “Golden Age” for the discovery of new antileishmanial agents: Current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. ChemMedChem 2021, 16 (11) , 1682-1696. https://doi.org/10.1002/cmdc.202100022
- Andris Evans, Kevin A. Kavanagh. Evaluation of metal-based antimicrobial compounds for the treatment of bacterial pathogens. Journal of Medical Microbiology 2021, 70 (5) https://doi.org/10.1099/jmm.0.001363
- Benjamin Rousselle, Florence Bouyer, Jérôme Bayardon, Myriam Laly, François Ghiringhelli, Yoann Rousselin, Ewen Bodio, Raluca Malacea-Kabbara. Development of a novel highly anti-proliferative family of gold complexes: Au( i )-phosphonium-phosphines. Dalton Transactions 2021, 50 (14) , 4880-4889. https://doi.org/10.1039/D0DT03708G
- François Mazars, Madalina Hrubaru, Nikolay Tumanov, Johan Wouters, Lionel Delaude. Synthesis of Azolium‐2‐dithiocarboxylate Zwitterions under Mild, Aerobic Conditions. European Journal of Organic Chemistry 2021, 2021 (13) , 2025-2033. https://doi.org/10.1002/ejoc.202100274
- Sidhali U. Parsekar, Paramita Haldar, P.K. Sudhadevi Antharjanam, Manjuri Kumar, Aditya P. Koley. Synthesis, characterization, crystal structure, DNA and human serum albumin interactions, as well as antiproliferative activity of a Cu(II) complex containing a Schiff base ligand formed in situ from the Cu(II)‐induced cyclization of 1,5‐bis(salicylidene)thiocarbohydrazide. Applied Organometallic Chemistry 2021, 35 (4) https://doi.org/10.1002/aoc.6152
- Caroline Marie Gallati, Sina Katharina Goetzfried, Anna Ortmeier, Jessica Sagasser, Klaus Wurst, Martin Hermann, Daniel Baecker, Brigitte Kircher, Ronald Gust. Synthesis, characterization and biological activity of bis[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2 H -imidazol-2-ylidene]gold( i ) complexes. Dalton Transactions 2021, 50 (12) , 4270-4279. https://doi.org/10.1039/D0DT03902K
- Rita Petrucci, Marta Feroci, Leonardo Mattiello, Isabella Chiarotto. Xanthine Scaffold: Available Synthesis Routes to Deliver Diversity by Derivatization. Mini-Reviews in Organic Chemistry 2021, 18 (1) , 27-42. https://doi.org/10.2174/1570193X17999200507103141
- Maria T. Proetto, Kelsey Alexander, Mohand Melaimi, Guy Bertrand, Nathan C. Gianneschi. Cyclic (Alkyl)(Amino)Carbene (CAAC) Gold(I) Complexes as Chemotherapeutic Agents. Chemistry – A European Journal 2021, 27 (11) , 3772-3778. https://doi.org/10.1002/chem.202004317
- Mohmmad Younus Wani, Manzoor Ahmad Malik. Chemistry of Gold. 2021, 69-79. https://doi.org/10.1007/978-981-33-6314-4_7
- Farjana Afroj. The Medicinal Chemistry of Metal-Containing Anticancer drugs. SSRN Electronic Journal 2021, 444 https://doi.org/10.2139/ssrn.3859521
- Clémence Rose, Laure Lichon, Morgane Daurat, Sébastien Clément, Magali Gary-Bobo, Sébastien Richeter. In vitro toxicity and photodynamic properties of porphyrinoids bearing imidazolium salts and N-heterocyclic carbene gold(I) complexes. Comptes Rendus. Chimie 2021, 24 (S3) , 83-99. https://doi.org/10.5802/crchim.98
- Mohmmad Younus Wani, Manzoor Ahmad Malik. Classes of Gold Complexes. 2021, 81-157. https://doi.org/10.1007/978-981-33-6314-4_8
- Xinlai Cheng, Stefanie Haeberle, Iart Luca Shytaj, Rodrigo. A. Gama-Brambila, Jannick Theobald, Shahrouz Ghafoory, Jessica Wölker, Uttara Basu, Claudia Schmidt, Annika Timm, Katerina Taškova, Andrea S. Bauer, Jörg Hoheisel, Nikolaos Tsopoulidis, Oliver T. Fackler, Andrea Savarino, Miguel A. Andrade-Navarro, Ingo Ott, Marina Lusic, Eva N. Hadaschik, Stefan. Wölfl. NHC-gold compounds mediate immune suppression through induction of AHR-TGFβ1 signalling in vitro and in scurfy mice. Communications Biology 2020, 3 (1) https://doi.org/10.1038/s42003-019-0716-8
- Maria Gil‐Moles, Uttara Basu, Rolf Büssing, Henrik Hoffmeister, Sebastian Türck, Agnieszka Varchmin, Ingo Ott. Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike‐ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**. Chemistry – A European Journal 2020, 26 (66) , 15140-15144. https://doi.org/10.1002/chem.202004112
- Bruno Dominelli, Christian H.G. Jakob, Jens Oberkofler, Pauline J. Fischer, Eva-Maria Esslinger, Robert M. Reich, Fernanda Marques, Teresa Pinheiro, João D.G. Correia, Fritz E. Kühn. Mechanisms underlying the cytotoxic activity of syn/anti-isomers of dinuclear Au(I) NHC complexes. European Journal of Medicinal Chemistry 2020, 203 , 112576. https://doi.org/10.1016/j.ejmech.2020.112576
- Wolfgang Walther, Dhiyaa Althagafi, Danielle Curran, Cillian O’Beirne, Cian Mc Carthy, Ingo Ott, Uttara Basu, Britta Büttner, Anja Sterner-Kock, Helge Müller-Bunz, Goar Sánchez-Sanz, Xiangming Zhu, Matthias Tacke. In-vitro and in-vivo investigations into the carbene-gold anticancer drug candidates NHC*-Au-SCSNMe2 and NHC*-Au-S-GLUC against advanced prostate cancer PC3. Anti-Cancer Drugs 2020, 31 (7) , 672-683. https://doi.org/10.1097/CAD.0000000000000930
- Adam A. Sulaiman, Ali Alhoshani, Homood M. As Sobeai, Meshal Alghanem, Ahmed K. Abogosh, Saeed Ahmad, Muhammad Altaf, Muhammad Monim-ul-Mehboob, Helen Stoeckli-Evans, Anvarhusein A. Isab. Anticancer activity and X-ray structure determination of gold(I) complexes of 2-(diphenylphosphanyl)-1-aminocyclohexane. Polyhedron 2020, 183 , 114532. https://doi.org/10.1016/j.poly.2020.114532
- Fatemeh Abyar, Leila Tabrizi. New cyclometalated gold (III) complex targeting thioredoxin reductase: exploring as cytotoxic agents and mechanistic insights. BioMetals 2020, 33 (2-3) , 107-122. https://doi.org/10.1007/s10534-020-00235-3
- Lena Koch, Darya Schmidt, Jörg Rust, Christian W. Lehmann, Fabian Mohr. Nickel(II) Phosphane‐ and N ‐heterocyclic Carbene Complexes with Tridentate, Dianionic [ S,N,O ] 2 – Ligands. Zeitschrift für anorganische und allgemeine Chemie 2020, 646 (10) , 469-474. https://doi.org/10.1002/zaac.202000130
- Caroline M. Gallati, Sina K. Goetzfried, Marjana Ausserer, Jessica Sagasser, Matthias Plangger, Klaus Wurst, Martin Hermann, Daniel Baecker, Brigitte Kircher, Ronald Gust. Synthesis, characterization and biological activity of bromido[3-ethyl-4-aryl-5-(2-methoxypyridin-5-yl)-1-propyl-1,3-dihydro-2 H -imidazol-2-ylidene]gold( i ) complexes. Dalton Transactions 2020, 49 (17) , 5471-5481. https://doi.org/10.1039/C9DT04824C
- Federica Guarra, Natalia Busto, Annalisa Guerri, Lorella Marchetti, Tiziano Marzo, Begoña García, Tarita Biver, Chiara Gabbiani. Cytotoxic Ag(I) and Au(I) NHC-carbenes bind DNA and show TrxR inhibition. Journal of Inorganic Biochemistry 2020, 205 , 110998. https://doi.org/10.1016/j.jinorgbio.2020.110998
- Sidhali U. Parsekar, Priyanka Velankanni, Shruti Sridhar, Paramita Haldar, Nayan A. Mate, Arnab Banerjee, P. K. Sudhadevi Antharjanam, Aditya P. Koley, Manjuri Kumar. Protein binding studies with human serum albumin, molecular docking and in vitro cytotoxicity studies using HeLa cervical carcinoma cells of Cu( ii )/Zn( ii ) complexes containing a carbohydrazone ligand. Dalton Transactions 2020, 49 (9) , 2947-2965. https://doi.org/10.1039/C9DT04656A
- Elisa Abas, Raquel Pena-Martinez, Diego Aguirre-Ramírez, Antonio Rodriguez-Dieguez, Mariano Laguna, Laura Grasa. New selective thiolate gold( i ) complexes inhibit the proliferation of different human cancer cells and induce apoptosis in primary cultures of mouse colon tumors. Dalton Transactions 2020, 49 (6) , 1915-1927. https://doi.org/10.1039/C9DT04423J
- Luis M. González-Barcia, Sandra Fernández-Fariña, Laura Rodríguez-Silva, Manuel R. Bermejo, Ana M. González-Noya, Rosa Pedrido. Comparative study of the antitumoral activity of phosphine-thiosemicarbazone gold(I) complexes obtained by different methodologies. Journal of Inorganic Biochemistry 2020, 203 , 110931. https://doi.org/10.1016/j.jinorgbio.2019.110931
- Manel Ouji, Sandra Bourgeade Delmas, Álvaro Fernández Álvarez, Jean‐Michel Augereau, Alexis Valentin, Catherine Hemmert, Heinz Gornitzka, Françoise Benoit‐Vical. Design, Synthesis and Efficacy of Hybrid Triclosan‐gold Based Molecules on Artemisinin‐resistant Plasmodium falciparum and Leishmania infantum Parasites. ChemistrySelect 2020, 5 (2) , 619-625. https://doi.org/10.1002/slct.201904345
- Ingo Ott. Metal N-heterocyclic carbene complexes in medicinal chemistry. 2020, 121-148. https://doi.org/10.1016/bs.adioch.2019.10.008
- Merve Gökşin Karaaslan, Aydın Aktaş, Canbolat Gürses, Yetkin Gök, Burhan Ateş. Chemistry, structure, and biological roles of Au-NHC complexes as TrxR inhibitors. Bioorganic Chemistry 2020, 95 , 103552. https://doi.org/10.1016/j.bioorg.2019.103552