COMPROBACIÓN DE LA HIPÓTESIS
3.5 DESARROLLO DE LA PROPUESTA
3.5.4 ORGANIZACIÓN DE LA PRODUCCIÓN
*E-Mails: [email protected] (M. P. R.), [email protected] (F. E. K.), [email protected] (A. C.)
ACKNOWLEDGEMENT
Ö.K. and J.B. gratefully acknowledge financial support by the TUM Graduate School and the Erasmus program. A.C. acknowledges support from Cardiff University and the Hans Fischer Senior Fellowship of the Technical University of Munich – Institute for Advanced Study, funded by the German Excellence Initiative and the European Union Seventh Framework Programme under grant agreement n° 291763. R.B. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 663830. The Erasmus program is also acknowledged for supporting the short-term scientific mission of M. J. L.B. to the University of Padova.
REFERENCES
(1) Rosenberg, B.; Van Camp, L.; Trosko, J. E.; Mansour, V. H. Platinum Compounds: A New Class of Potent Antitumour Agents. Nature 1969, 222 (5191), 385–386 DOI: 10.1038/222385a0.
(2) Kelland, L. The Resurgence of Platinum-Based Cancer Chemotherapy. Nat. Rev. Cancer 2007, 7 (8), 573–584 DOI: 10.1038/nrc2167.
(3) Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular Mechanisms of Cisplatin Resistance. Oncogene 2012, 31 (15), 1869–1883 DOI: 10.1038/onc.2011.384.
(4) Widakowich, C.; de Castro, G.; de Azambuja, E.; Dinh, P.; Awada, A. Review: Side Effects of Approved Molecular Targeted Therapies in Solid Cancers. Oncologist 2007, 12 (12), 1443–1455 DOI: 10.1634/theoncologist.12-12-1443.
(5) Barabas, K.; Milner, R.; Lurie, D.; Adin, C. Cisplatin: A Review of Toxicities and Therapeutic Applications. Vet. Comp. Oncol. 2008, 6 (1), 1–18 DOI: 10.1111/j.1476- 5829.2007.00142.x.
(6) Reedijk, J. Platinum Anticancer Coordination Compounds: Study of DNA Binding Inspires New Drug Design. Eur. J. Inorg. Chem. 2009, No. 10, 1303–1312 DOI: 10.1002/ejic.200900054.
(7) Barefoot, R. R. Speciation of Platinum Compounds: A Review of Recent Applications in Studies of Platinum Anticancer Drugs. J. Chromatogr. B Biomed. Sci. Appl. 2001, 751 (2), 205–211 DOI: 10.1016/S0378-4347(00)00498-9.
(8) Wang, D.; Lippard, S. J. Cellular Processing of Platinum Anticancer Drugs. Nat. Rev. Drug Deliv. 2005, 4 (4), 307–320 DOI: 10.1038/nrd1691.
(9) Guerriero, A.; Oberhauser, W.; Riedel, T.; Peruzzini, M.; Dyson, P. J.; Gonsalvi, L. New Class of Half-Sandwich Ruthenium(II) Arene Complexes Bearing the Water- Soluble CAP Ligand as an in Vitro Anticancer Agent. Inorg. Chem. 2017, No. Ii, acs.inorgchem.7b00915 DOI: 10.1021/acs.inorgchem.7b00915.
(10) Yang, C.; Wang, W.; Liang, J.-X.; Li, G.; Vellaisamy, K.; Wong, C.-Y.; Ma, D.-L.; Leung, C.-H. A Rhodium(III)-Based Inhibitor of Lysine-Specific Histone Demethylase 1 as an Epigenetic Modulator in Prostate Cancer Cells. J. Med. Chem. 2017, 60 (6), 2597–2603 DOI: 10.1021/acs.jmedchem.7b00133.
(11) Prosser, K. E.; Chang, S. W.; Saraci, F.; Le, P. H.; Walsby, C. J. Anticancer Copper Pyridine Benzimidazole Complexes: ROS Generation, Biomolecule Interactions, and Cytotoxicity. J. Inorg. Biochem. 2017, 167, 89–99 DOI:
10.1016/j.jinorgbio.2016.11.006.
(12) Haque, R. A.; Choo, S. Y.; Budagumpi, S.; Iqbal, M. A.; Al-Ashraf Abdullah, A. Silver(I) Complexes of Mono-and Bidentate N-Heterocyclic Carbene Ligands:
Synthesis, Crystal Structures, and in Vitro Antibacterial and Anticancer Studies. Eur. J. Med. Chem. 2015, 90, 82–92 DOI: 10.1016/j.ejmech.2014.11.005.
(13) Muhammad, N.; Guo, Z. Metal-Based Anticancer Chemotherapeutic Agents. Curr. Opin. Chem. Biol. 2014, 19 (1), 144–153 DOI: 10.1016/j.cbpa.2014.02.003.
(14) Gasser, G.; Ott, I.; Metzler-Nolte, N. Organometallic Anticancer Compounds. J. Med. Chem. 2011, 54 (1), 3–25 DOI: 10.1021/jm100020w.
(15) Hartinger, C. G.; Metzler-nolte, N.; Dyson, P. J. Challenges and Opportunities in the Development of Organometallic Anticancer Drugs. 2012 DOI: 10.1021/om300373t. (16) Lazarević, T.; Rilak, A.; Bugarčić, Ž. D. Platinum, Palladium, Gold and Ruthenium
Complexes as Anticancer Agents: Current Clinical Uses, Cytotoxicity Studies and Future Perspectives. Eur. J. Med. Chem. 2017 DOI: 10.1016/j.ejmech.2017.04.007. (17) Romero-Canelón, I.; Sadler, P. J. Next-Generation Metal Anticancer Complexes:
Multitargeting via Redox Modulation. Inorg. Chem. 2013, 52 (21), 12276–12291 DOI: 10.1021/ic400835n.
(18) Bruijnincx, P. C.; Sadler, P. J. New Trends for Metal Complexes with Anticancer Activity. Curr. Opin. Chem. Biol. 2008, 12 (2), 197–206 DOI:
10.1016/j.cbpa.2007.11.013.
(19) Nobili, S.; Mini, E.; Landini, I.; Gabbiani, C.; Casini, A.; Messori, L. Gold Compounds as AnticancerAgents: Chemistry, Cellular Pharmacology, and Preclinical Studies. Med. Res. Rev. 2010, 30 (3), 550–580 DOI: 10.1002/med.20168.
(20) Casini, A.; Messori, L. Molecular Mechanisms and Proposed Targets for Selected Anticancer Gold Compounds. Curr. Top. Med. Chem. 2011, 11 (21), 2647–2660 DOI: 10.2174/156802611798040732.
(21) Bertrand, B.; Casini, A. A Golden Future in Medicinal Inorganic Chemistry: The Promise of Anticancer Gold Organometallic Compounds. Dalton Trans. 2014, 43, 4209–4219 DOI: 10.1039/c3dt52524d.
(22) Zou, T.; Ching, A.; Lum, T.; Lok, C.-N.; Zhang, J.-J.; Che, C.-M. Chemical Biology of Anticancer gold(III) and gold(I) Complexes. Chem. Soc. Rev 2015, 44 (24), 8786–8801 DOI: 10.1039/c5cs00132c.
Age. Drugs R D 2015, 15 (1), 13–20 DOI: 10.1007/s40268-015-0083-y.
(24) Simon, T. M.; Kunishima, D. H.; Vibert, G. J.; Lorber, A. Screening Trial with the Coordinated Gold Compound Auranofin Using Mouse Lymphocytic Leukemia p388. Cancer Res. 1981, 41 (1), 94–97.
(25) Biot, C.; Castro, W.; Botté, C. Y.; Navarro, M. The Therapeutic Potential of Metal- Based Antimalarial Agents: Implications for the Mechanism of Action. Dalt. Trans. 2012, 41 (21), 6335 DOI: 10.1039/c2dt12247b.
(26) Sannella, A. R.; Casini, A.; Gabbiani, C.; Messori, L.; Bilia, A. R.; Vincieri, F. F.; Majori, G.; Severini, C. New Uses for Old Drugs. Auranofin, a Clinically Established Antiarthritic Metallodrug, Exhibits Potent Antimalarial Effects in Vitro: Mechanistic and Pharmacological Implications. FEBS Lett. 2008, 582 (6), 844–847 DOI:
10.1016/j.febslet.2008.02.028.
(27) Mphahlele, M.; Papathanasopoulos, M.; Cinellu, M. A.; Coyanis, M.; Mosebi, S.; Traut, T.; Modise, R.; Coates, J.; Hewer, R. Modification of HIV-1 Reverse
Transcriptase and Integrase Activity by gold(III) Complexes in Direct Biochemical Assays. Bioorganic Med. Chem. 2012, 20 (1), 401–407 DOI:
10.1016/j.bmc.2011.10.072.
(28) Herrmann, W. a. N-Heterocyclic Carbenes: A New Concept in Organometallic Catalysis13. Angew. Chemie Int. Ed. 2002, 41 (8), 1290–1309 DOI: 10.1002/1521- 3773(20020415)41:8<1290::AID-ANIE1290>3.0.CO;2-Y.
(29) Liu, W.; Gust, R. Update on Metal N-Heterocyclic Carbene Complexes as Potential Anti-Tumor Metallodrugs. Coord. Chem. Rev. 2016, 329, 191–213 DOI:
10.1016/j.ccr.2016.09.004.
(30) Oehninger, L.; Rubbiani, R.; Ott, I. N-Heterocyclic Carbene Metal Complexes in Medicinal Chemistry. Dalt. Trans. 2013, 42 (10), 3269–3284 DOI:
(31) Muenzner, J. K.; Biersack, B.; Albrecht, A.; Rehm, T.; Lacher, U.; Milius, W.; Casini, A.; Zhang, J.; Ott, I. Ferrocenyl-Coupled N-Heterocyclic Carbene Complexes of Gold ( I ): A Successful Approach to Multinuclear Anticancer Drugs. 2016, 22 (52), 18953– 18962 DOI: 10.1002/chem.201604246.
(32) De Almeida, A.; Oliveira, B. L.; Correia, J. D. G.; Soveral, G.; Casini, A. Emerging Protein Targets for Metal-Based Pharmaceutical Agents: An Update. Coord. Chem. Rev. 2013, 257 (19–20), 2689–2704 DOI: 10.1016/j.ccr.2013.01.031.
(33) Mendes, F.; Groessl, M.; Nazarov, A. A.; Tsybin, Y. O.; Sava, G.; Santos, I.; Dyson, P. J.; Casini, A. Metal-Based Inhibition of poly(ADP-Ribose) Polymerase-the Guardian Angel of DNA. J. Med. Chem. 2011, 54 (7), 2196–2206 DOI: 10.1021/jm2000135. (34) Citta, A.; Scalcon, V.; Göbel, P.; Bertrand, B.; Wenzel, M.; Folda, A.; Rigobello, M.
P.; Meggers, E.; Casini, A. Toward Anticancer Gold-Based Compounds Targeting PARP-1: A New Case Study. RSC Adv. 2016, 6 (82), 79147–79152 DOI:
10.1039/C6RA11606J.
(35) Holenya, P.; Can, S.; Rubbiani, R.; Alborzinia, H.; Jünger, A.; Cheng, X.; Ott, I.; Wölfl, S. Detailed Analysis of pro-Apoptotic Signaling and Metabolic Adaptation Triggered by a N-Heterocyclic Carbene–gold( <scp>i</scp> ) Complex. Metallomics 2014, 6 (9), 1591–1601 DOI: 10.1039/C4MT00075G.
(36) Matsui, M.; Oshima, M.; Oshima, H.; Takaku, K.; Maruyama, T.; Yodoi, J.; Taketo, M. M. Early Embryonic Lethality Caused by Targeted Disruption of the Mouse Thioredoxin Gene. Dev. Biol. 1996, 178 (1), 179–185 DOI: 10.1006/dbio.1996.0208. (37) Mustacich, D.; Powis, G. Thioredoxin Reductase. Biochem. J. 2000, 346 Pt 1, 1–8
DOI: 10.1042/0264-6021:3460001.
(38) Lillig, C. H.; Holmgren, A. Thioredoxin and Related Molecules–From Biology to Health and Disease. Antioxid. Redox Signal. 2006, 9 (1), 25–47 DOI:
(39) Nakamura, H.; Bai, J.; Nishinaka, Y.; Ueda, S.; Sasada, T.; Ohshio, G.; Imamura, M.; Takabayashi, A.; Yamaoka, Y.; Yodoi, J. Expression of Thioredoxin and Glutaredoxin, Redox-Regulating Proteins, in Pancreatic Cancer. Cancer Detect. Prev. 2000, 24 (1), 53–60.
(40) Berggren, M.; Gallegos, A.; Gasdaska, J. R.; Gasdaska, P. Y.; Warneke, J.; Powis, G. Thioredoxin and Thioredoxin Reductase Gene Expression in Human Tumors and Cell Lines, and the Effects of Serum Stimulation and Hypoxia. Anticancer Res. 1996, 16 (6B), 3459–3466.
(41) Lu, J.; Holmgren, A. The Thioredoxin Antioxidant System. Free Radic. Biol. Med. 2014, 66, 75–87 DOI: 10.1016/j.freeradbiomed.2013.07.036.
(42) Holmgren, A.; Lu, J. Thioredoxin and Thioredoxin Reductase: Current Research with Special Reference to Human Disease. Biochem. Biophys. Res. Commun. 2010, 396 (1), 120–124 DOI: 10.1016/j.bbrc.2010.03.083.
(43) Bertrand, B.; Stefan, L.; Pirrotta, M.; Monchaud, D.; Bodio, E.; Richard, P.; Le
Gendre, P.; Warmerdam, E.; de Jager, M. H.; Groothuis, G. M. M.; Picquet, M.; Casini, A. Caffeine-Based gold(I) N-Heterocyclic Carbenes as Possible Anticancer Agents: Synthesis and Biological Properties. Inorg. Chem. 2014, 53 (I), 2296–2303 DOI: 10.1021/ic403011h.
(44) Bazzicalupi, C.; Ferraroni, M.; Papi, F.; Massai, L.; Bertrand, B.; Messori, L.; Gratteri, P.; Casini, A. Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G-Quadruplex: A Joint ESI MS and XRD Investigation. Angew. Chemie - Int. Ed. 2016, 55 (13), 4256–4259 DOI:
10.1002/anie.201511999.
(45) Karaca, Ö.; Meier-Menches, S. M.; Casini, A.; Kühn, F. E. On the Binding Modes of Metal NHC Complexes with DNA Secondary Structures: Implications for Therapy and Imaging. Chem. Commun. 2017, 53 (59), 8249–8260 DOI: 10.1039/C7CC03074F.
(46) Chen, Z. F.; Qin, Q. P.; Qin, J. L.; Zhou, J.; Li, Y. L.; Li, N.; Liu, Y. C.; Liang, H. Water-Soluble Ruthenium(II) Complexes with Chiral 4-(2,3-Dihydroxypropyl)- Formamide Oxoaporphine (FOA): In Vitro and in Vivo Anticancer Activity by
Stabilization of G-Quadruplex DNA, Inhibition of Telomerase Activity, and Induction of Tumor Cell Apoptosis. J. Med. Chem. 2015, 58 (11), 4771–4789 DOI:
10.1021/acs.jmedchem.5b00444.
(47) Montani, M.; Badillo, G. V; Hysi, A.; Lupidi, G.; Pettinari, R.; Gambini, V.; Tilio, M.; Marchetti, F.; Pettinari, C.; Ferraro, S.; Iezzi, M.; Marchini, C.; Amici, A. The Water Soluble Ruthenium ( II ) Organometallic Compound [ Ru ( P -Cymene )( Bis ( 3 , 5 Dimethylpyrazol-1-Yl ) Methane ) Cl ] Cl Suppresses Triple Negative Breast Cancer Growth by Inhibiting Tumor Infiltration of Regulatory T Cells. 2016, 107, 282–290. (48) Battistin, F.; Scaletti, F.; Balducci, G.; Pillozzi, S.; Arcangeli, A.; Messori, L.; Alessio,
E. Water-Soluble Ru ( II ) - and Ru ( III ) -Halide-PTA Complexes Biological Properties. 2016, 160, 180–188.
(49) Rilak, A.; Bratsos, I.; Zangrando, E.; Kljun, J.; Turel, I.; Bugarčić, Ž. D.; Alessio, E. New Water-Soluble ruthenium(II) Terpyridine Complexes for Anticancer Activity: Synthesis, Characterization, Activation Kinetics, and Interaction with Guanine Derivatives. Inorg. Chem. 2014, 53 (12), 6113–6126 DOI: 10.1021/ic5005215. (50) Liaw, W.; Chen, C.; Lee, G.; Peng, S. Synthesis, Characterization, and in Vitro
Cytotoxicity of Some Gold(I) and Trans Platinum(II) Thionate Complexes Containing Water-Soluble PTA and DAPTA Ligands. X-Ray Crystal Structures of
[Au(SC4H3N2)(PTA)], Trans-[Pt(SC4H3N2)2(PTA)2], Trans-[Pt(SC5H4N)2. Inorg. Chem. 2008, 47 (13), 5641–5648 DOI: 10.1021/ic7021903.
(51) Yap, S. Q.; Chin, C. F.; Hong Thng, A. H.; Pang, Y. Y.; Ho, H. K.; Ang, W. H. Finely Tuned Asymmetric Platinum(IV) Anticancer Complexes: Structure–Activity
(4), 300–311 DOI: 10.1002/cmdc.201600577.
(52) Thornton, L.; Dixit, V.; Assad, L. O. N.; Ribeiro, T. P.; Queiroz, D. D.; Kellett, A.; Casey, A.; Colleran, J.; Pereira, M. D.; Rochford, G.; McCann, M.; O’Shea, D.; Dempsey, R.; McClean, S.; Kia, A. F. A.; Walsh, M.; Creaven, B.; Howe, O.; Devereux, M. Water-Soluble and Photo-Stable silver(I) Dicarboxylate Complexes Containing 1,10-Phenanthroline Ligands: Antimicrobial and Anticancer
Chemotherapeutic Potential, DNA Interactions and Antioxidant Activity. J. Inorg. Biochem. 2016, 159, 120–132 DOI: 10.1016/j.jinorgbio.2016.02.024.
(53) Vergara, E.; Casini, A.; Sorrentino, F.; Zava, O.; Cerrada, E.; Rigobello, M. P.; Bindoli, A.; Laguna, M.; Dyson, P. J. Anticancer Therapeutics That Target
Selenoenzymes: Synthesis, Characterization, in Vitro Cytotoxicity, and Thioredoxin Reductase Inhibition of a Series of gold(I) Complexes Containing Hydrophilic Phosphine Ligands. ChemMedChem 2010, 5 (1), 96–102 DOI:
10.1002/cmdc.200900370.
(54) Rackham, O.; Nichols, S. J.; Leedman, P. J.; Berners-Price, S. J.; Filipovska, A. A gold(I) Phosphine Complex Selectively Induces Apoptosis in Breast Cancer Cells: Implications for Anticancer Therapeutics Targeted to Mitochondria. Biochem. Pharmacol. 2007, 74 (7), 992–1002 DOI: 10.1016/j.bcp.2007.07.022.
(55) Zou, T.; Lum, C. T.; Chui, S. S. Y.; Che, C. M. Gold(III) Complexes Containing N- Heterocyclic Carbene Ligands: Thiol “switch-On” fluorescent Probes and Anti-Cancer Agents. Angew. Chemie - Int. Ed. 2013, 52 (10), 2930–2933 DOI:
10.1002/anie.201209787.
(56) García-Moreno, E.; Gascón, S.; Atrián-Blasco, E.; Rodriguez-Yoldi, M. J.; Cerrada, E.; Laguna, M. Gold(I) Complexes with Alkylated PTA (1,3,5-Triaza-7-
Phosphaadamantane) Phosphanes as Anticancer Metallodrugs. Eur. J. Med. Chem. 2014, 79, 164–172 DOI: 10.1016/j.ejmech.2014.04.001.
(57) Wetzel, C.; Kunz, P. C.; Kassack, M. U.; Hamacher, A.; Böhler, P.; Watjen, W.; Ott, I.; Rubbiani, R.; Spingler, B. Gold(I) Complexes of Water-Soluble Diphos-Type Ligands: Synthesis, Anticancer Activity, Apoptosis and Thioredoxin Reductase Inhibition. Dalton Trans. 2011, 40 (36), 9212–9220 DOI: 10.1039/c1dt10368g.
(58) Vergara, E.; Cerrada, E.; Casini, A.; Zava, O.; Laguna, M.; Dyson, P. J.
Antiproliferative Activity of gold(I) Alkyne Complexes Containing Water-Soluble Phosphane Ligands. Organometallics 2010, 29 (11), 2596–2603 DOI:
10.1021/om100300a.
(59) Pellei, M.; Gandin, V.; Marinelli, M.; Marzano, C.; Yousufuddin, M.; Dias, H. V. R.; Santini, C. 2012- Synthesis and Biological Activity of Ester- and Amide-
Functionalized Imidazolium Salts and Related Water-Soluble Coinage Metal N‑ Heterocyclic Carbene Complexes. 2012.
(60) Wang, H. M. J.; Lin, I. J. B. Facile Synthesis of Silver(I)−Carbene Complexes. Useful Carbene Transfer Agents. Organometallics 1998, 17 (5), 972–975 DOI:
10.1021/om9709704.
(61) Azua, A.; Sanz, S.; Peris, E. Sulfonate-Functionalized NHC-Based Ruthenium Catalysts for the Isomerization of Allylic Alcohols in Water. Recyclability Studies. Organometallics 2010, 29 (16), 3661–3664 DOI: 10.1021/om100601r.
(62) Prajapati, D.; Schulzke, C.; Kindermann, M. K.; Kapdi, A. R. Selective Palladium- Catalysed Arylation of 2,6-Dibromopyridine Using N-Heterocyclic Carbene Ligands. RSC Adv. 2015, 5 (65), 53073–53085 DOI: 10.1039/C5RA10561G.
(63) Almássy, A.; Nagy, C. E.; Bényei, A. C.; Joó, F. Novel Sulfonated N-Heterocyclic Carbene gold(I) Complexes: Homogeneous Gold Catalysis for the Hydration of
Terminal Alkynes in Aqueous Media. Organometallics 2010, 29 (11), 2484–2490 DOI: 10.1021/om1001292.
Gebbink, R. J. M. One-Pot Synthesis and Immobilisation of Sulfonate-Tethered N- Heterocyclic Carbene Complexes on Polycationic Dendrimers. Chem. - A Eur. J. 2009, 15 (39), 9981–9986 DOI: 10.1002/chem.200901719.
(65) Papini, G.; Pellei, M.; Lobbia, G. G.; Burini, A.; Santini, C. Sulfonate- or Carboxylate- Functionalized N-Heterocyclic Bis-Carbene Ligands and Related Water Soluble Silver Complexes. Dalt. Trans. 2009, No. 35, 6985–6990 DOI: 10.1039/b906994a.
(66) Moore, L. R.; Cooks, S. M.; Anderson, M. S.; Schanz, H. J.; Griffin, S. T.; Rogers, R. D.; Kirk, M. C.; Shaughnessy, K. H. Synthesis and Characterization of Water-Soluble Silver and Palladium Imidazol-2-Ylidene Complexes with Noncoordinating Anionic Substituents. Organometallics 2006, 25 (21), 5151–5158 DOI: 10.1021/om060552b. (67) Fernández, G. A.; Picco, A.; Ceolín, M. R.; Chopa, A. B.; Silbestri, G. F. Synthesis and
Structural Characterization of Water-Soluble Gold(I) N-Heterocyclic Carbene Complexes. An X-Ray Absorption Fine Structure Spectroscopy (XAFS) Study. Organometallics 2013, 32 (I), 6315–6323 DOI: 10.1021/om400663a.
(68) Jantke, D.; Cokoja, M.; Pöthig, A.; Herrmann, W. A.; Kuhn, F. E. Synthesis and Characterization of Highly Water Soluble Ruthenium(II) and Osmium(II) Complexes Bearing Chelating Sulfonated N ‑ Heterocyclic Carbene Ligands. Organometallics 2013, 32, 741–744 DOI: 10.1021/om301218k.
(69) Torregrosa, R.; Pastor, I. M.; Yus, M. Solvent-Free Direct Regioselective Ring Opening of Epoxides with Imidazoles. Tetrahedron 2007, 63 (2), 469–473 DOI: 10.1016/j.tet.2006.10.055.
(70) Bartoszewicz, A.; Marcos, R.; Sahoo, S.; Inge, A. K.; Zou, X.; Mart??n-Matute, B. A Highly Active Bifunctional Iridium Complex with an Alcohol/alkoxide- Tethered N- Heterocyclic Carbene for Alkylation of Amines with Alcohols. Chem. - A Eur. J. 2012, 18 (45), 14510–14519 DOI: 10.1002/chem.201201845.
Studies of Ligand Exchange in N-Heterocyclic Carbene silver(I) Complexes. Organometallics 2012, 31 (10), 4063–4071 DOI: 10.1021/om300340w.
(72) Citta, A.; Schuh, E.; Mohr, F.; Folda, A.; Massimino, M. L.; Bindoli, A.; Casini, A.; Rigobello, M. P. Fluorescent silver(I) and gold(I) N-Heterocyclic Carbene Complexes with Cytotoxic Properties: Mechanistic Insights. Metallomics 2013, 5 (8), 1006–1015 DOI: 10.1039/c3mt20260g.
(73) Schuh, E.; Pflüger, C.; Citta, A.; Folda, A.; Rigobello, M. P.; Bindoli, A.; Casini, A.; Mohr, F. Gold(I) Carbene Complexes Causing Thioredoxin 1 and Thioredoxin 2 Oxidation as Potential Anticancer Agents. J. Med. Chem. 2012, 55 (11), 5518–5528 DOI: 10.1021/jm300428v.
(74) Rubbiani, R.; Can, S.; Kitanovic, I.; Alborzinia, H.; Stefanopoulou, M.; Can, S.; Kitanovic, A.; Onambele, L. a.; Stefanopoulou, M.; Geldmacher, Y.; Sheldrick, W. S.; Wolber, G.; Prokop, A.; Wölfl, S.; Ott, I. Supporting Information Comparative In Vitro Evaluation of N-Heterocyclic Carbene Gold ( I ) Complexes of the
Benzimidazolylidene Type. J. Med. Chem. 2010, 53 (I), 8608–8618 DOI: 10.1021/jm100801e.
(75) Rubbiani, R.; Salassa, L.; De Almeida, A.; Casini, A.; Ott, I. Cytotoxic gold(I) N- Heterocyclic Carbene Complexes with Phosphane Ligands as Potent Enzyme
Inhibitors. ChemMedChem 2014, 9 (6), 1205–1210 DOI: 10.1002/cmdc.201400056. (76) Schmidt, C.; Karge, B.; Misgeld, R.; Prokop, A.; Franke, R.; Brönstrup, M.; Ott, I.
Gold(I) NHC Complexes: Antiproliferative Activity, Cellular Uptake, Inhibition of Mammalian and Bacterial Thioredoxin Reductases, and Gram-Positive Directed Antibacterial Effects. Chem. - A Eur. J. 2017, 23 (8), 1869–1880 DOI:
10.1002/chem.201604512.
(77) Benesch, R. E.; Benesch, R. The Acid Strength of the -SH Group in Cysteine and Related Compounds. J. Am. Chem. Soc. 1955, 77, 5877–5881.
(78) Huber, R. E.; Benesch, R. Comparison of the Chemical Properties of Selenocysteine and Selenocystine with Their Sulfur Analogs. Arch. Biochem. Biophys. 1967, 122, 164–173.
(79) Hartinger, C. G.; Groessl, M.; Meier, S. M.; Casini, A.; Dyson, P. J. Application of Mass Spectrometric Techniques to Delineate the Modes-of-Action of Anticancer Metallodrugs. Chem. Soc. Rev. 2013, 42 (14), 6186–6199 DOI: 10.1039/c3cs35532b. (80) Wenzel, M.; Casini, A. Mass Spectrometry as a Powerful Tool to Study Therapeutic
Metallodrugs Speciation Mechanisms: Current Frontiers and Perspectives. Coord. Chem. Rev. 2017, In Press DOI: 10.1016/j.ccr.2017.02.012.
(81) Meier, S. M.; Gerner, C.; Keppler, B. K.; Cinellu, M. A.; Casini, A. Mass Spectrometry Uncovers Molecular Reactivities of Coordination and Organometallic Gold(III) Drug Candidates in Competitive Experiments That Correlate with Their Biological Effects. Inorg. Chem. 2016, 55 (9), 4248–4259 DOI: 10.1021/acs.inorgchem.5b03000.
(82) Bindoli, A.; Rigobello, M. P.; Scutari, G.; Gabbiani, C.; Casini, A.; Messori, L.
Thioredoxin Reductase: A Target for Gold Compounds Acting as Potential Anticancer Drugs. Coord. Chem. Rev. 2009, 253 (11–12), 1692–1707 DOI:
10.1016/j.ccr.2009.02.026.
(83) Estrada-Ortiz, N.; Guarra, F.; DeGraaf, I. A. M.; Marchetti, L.; DeJager, M. H.; Groothuis, G. M. M.; Gabbiani, C.; Casini, A. Anticancer 1 Gold N-Heterocyclic Carbene Complexes: A 2 Comparative in Vitro and Ex Vivo Study. ChemMedChem 2017, 12 (17), 1429–1435 DOI: 10.1002/cmdc.201700316.
(84) Occhipinti, G.; Jensen, V. R.; Törnroos, K. W.; Frøystein, N. Å.; Bjørsvik, H. R. Synthesis of a New Bidentate NHC-Ag(I) Complex and Its Unanticipated Reaction with the Hoveyda-Grubbs First Generation Catalyst. Tetrahedron 2009, 65 (34), 7186– 7194 DOI: 10.1016/j.tet.2009.05.095.
Purification and Characterization. Biochemistry 1982, 21 (26), 6628–6633 DOI: 10.1021/bi00269a003.
(86) Rigobello, M. P.; Bindoli, A. Pt B: Cellular Localization and Signaling. In Methods in Enzymology: Thiol Redox Transitions in Cell Signaling; Cadenas, E., Packer, L., Eds.; 2010; pp 109–122.
(87) Lowry, O. H.; Rosebrough, N. J.; Farr, A. L.; Randall, R. J. Protein Measurement with the Folin Phenol Reagent. J. Biol. Chem. 1951, 193 (1), 265–275 DOI: 10.1016/0304- 3894(92)87011-4.
(88) Fang, J.; Lu, J.; Holmgren, A. Thioredoxin Reductase Is Irreversibly Modified by Curcumin: A Novel Molecular Mechanism for Its Anticancer Activity. J. Biol. Chem. 2005, 280 (26), 25284–25290 DOI: 10.1074/jbc.M414645200.
Table of Contents Graphic: For Table of Contents Only
Table of Contents Synopsis.
The synthesis of novel hydrophilic gold(I) NHC complexes is reported. Selected compounds distinctly target the pivotal biological target thioredoxin reductase (TrxR) in the nanomolar range as benchmark anticancer drug auranofin, and exhibit remarkable antiproliferative effects against human ovarian cancer cells.