Synthesis, Molecular Docking and Cytotoxic Activity Evaluation of Organometallic Thiolated Gold(I) Complexes

Document Type : Research article


1 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

3 Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4 Department of Medicinal Chemistry, School of Pharmacy Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.


The complex [(PhCH2NC)AuCl], 1, was prepared by the reaction of [(Me2S)AuCl], A, with an equimolar amount of benzyl isocyanide (PhCH2NC) ligand. Through a salt metathesis reaction, the chloride ligand in 1 was replaced by potassium benzothiazole-2-thiolate (Kbt) and potassium benzoimidazole-2-thiolate (Kbi) to afford complexes (PhCH2NC)Au(κ1-S-bt)], 2a and (PhCH2NC)Au(κ1-S-bi)], 2b, respectively, which were characterized by NMR spectroscopy. The cytotoxic activities of 2a and 2b were evaluated against three human cancer cell lines, including A549 (lung), SKOV3 (ovary), and MCF-7 (breast). Our results indicated that 2a exhibited comparable cytotoxicity on investigated cell lines with cisplatin. It showed a good anti-proliferative activity with IC50 of 19.46, 11.76 and 13.27 μM against A549, SKOV3 and MCF-7 cell lines, respectively. The effects of these complexes on the proliferation of the non-tumorigenic epithelial breast cell line (MCF-10A) showed their good selectivity between the tumorigenic and non-tumorigenic cell lines. Molecular docking simulation studies were also conducted to determine the specific binding site and binding mode of the synthesized gold complexes to DNA and thioredoxinreductase (TrxR) as their proposed targets.                                                                                                                                                

Graphical Abstract

Synthesis, Molecular Docking and Cytotoxic Activity Evaluation of Organometallic Thiolated Gold(I) Complexes


(1)        Fong CW. Molecular mechanisms of cellular transport, resistance and cytotoxic side effects of platinum and adjuvant anti-cancer drugs–a molecular orbital study. J. Comput. Chem. (2017) 3: 185.
(2)        Santabarbara G, Maione P, Rossi A and Gridelli C. Pharmacotherapeutic options for treating adverse effects of Cisplatin chemotherapy. Expert Opin. Pharmacother. (2016) 17: 561-70.
(3)        Nardon C, Boscutti G and Fregona D. Beyond Platinums: gold complexes as anticancer agents. Anticancer Res. (2014) 34: 487-92.
(4)        Raubenheimer HG and Schmidbaur H. The late start and amazing upswing in gold chemistry. J. Chem. Educ. (2014) 91: 2024-36.
(5)        Đurović MD, Bugarčić ŽD and van Eldik R. Stability and reactivity of gold compounds – From fundamental aspects to applications. Coord. Chem. Rev. (2017) 338: 186-206.
(6)        Hutchings GJ, Brust M and Schmidbaur H. Gold-an introductory perspective. Chem. Soc. Rev. (2008) 37: 1759-65.
(7)        Mohr F. Gold Chemistry: Applications and Future Directions in the Life Sciences. 2nd ed. Wiley-VCH Publisher, New Jersey (2009) 47-92.
(8)        Laguna A, Modern Supramolecular Gold Chemistry: Gold-Metal Interactions and Applications. Wiley-VCH Publisher, New Jersey (2008) 1-63.
(9)        Schmidbaur H. Ludwig Mond Lecture. High-carat gold compounds. Chem. Soc. Rev. (1995) 24: 391-400.
(10)      Hao L, Mansour MA, Lachicotte RJ, Gysling HJ and Eisenberg R. A gold(I) mononuclear complex and its association into binuclear and cluster compounds by hydrogen bonding or metal ion coordination. Inorg. Chem. (2000) 39: 5520-9.
(11)      Robson JA, Gonzàlez de Rivera F, Jantan KA, Wenzel MN, White AJP, Rossell O and Wilton-Ely JDET. Bifunctional chalcogen linkers for the stepwise generation of multimetallic assemblies and functionalized nanoparticles. Inorg. Chem. (2016) 55: 12982-96.
(12)      Zou T, Lum CT, Lok CN, Zhang JJ and Che CM. Chemical biology of anticancer gold(III) and gold(I) complexes. Chem. Soc. Rev. (2015) 44: 8786-801.
(13)      Atrián-Blasco E, Gascón S, Rodrı́guez-Yoldi MJ, Laguna M and Cerrada E. Novel gold(I) thiolate derivatives synergistic with 5-fluorouracil as potential selective anticancer agents in colon cancer. Inorg. Chem. (2017) 56: 8562-79.
(14)      Malwitz MA, Lim SH, White-Morris RL, Pham DM, Olmstead MM and Balch AL. Crystallization and interconversions of vapor-sensitive, luminescent polymorphs of [(C6H11NC)2AuI](AsF6) and [(C6H11NC)2AuI](PF6). J. Am. Chem. Soc. (2012) 134: 10885-93.
(15)      Schneider W, Angermaier K, Sladek A and Schmidbaur H. Ligand influences on the Supramolecular chemistry of simple gold(I) complexes: mononuclear (Isonitrile)gold(I) complexes. Z. Naturforsch. B (1996) 51: 790-800.
(16)      Manzano R, Rominger F and Hashmi ASK. Saturated abnormal NHC–Gold(I) complexes: synthesis and catalytic activity. Organometallics (2013) 32: 2199-203.
(17)      Collado A, Gomez-Suarez A, Martin AR, Slawin AMZ and Nolan SP. Straightforward synthesis of [Au(NHC)X] (NHC = N-heterocyclic carbene, X = Cl, Br, I) complexes. Chem. Commun. (2013) 49: 5541-3.
(18)      Han Z, Bates JI, Strehl D, Patrick BO and Gates DP. Homo- and heteropolynuclear complexes containing bidentate bridging 4-phosphino-N-heterocyclic carbene ligands. Inorg. Chem. (2016) 55: 5071-8.
(19)      Seki T, Sakurada K, Muromoto M, Seki S and Ito H. Detailed investigation of the structural, thermal, and electronic properties of gold isocyanide complexes with mechano-triggered single-crystal-to-single-crystal phase transitions. Chem. Eur. J. (2016) 22: 1968-78.
(20)      Johnson A and Gimeno MC. An efficient and sustainable synthesis of NHC gold complexes. Chem. Commun. (2016) 52: 9664-7.
(21)      Ott I. On the medicinal chemistry of gold complexes as anticancer drugs. Coord. Chem. Rev. (2009) 253: 1670-81.
(22)      Joao Carlos L and Laura R. Phosphine-gold(I) compounds as anticancer agents: general description and mechanisms of action. Anti-Cancer Agents Med. Chem. (2011) 11: 921-8.
(23)      García-Moreno E, Gascón S, Atrián-Blasco E, Rodriguez-Yoldi MJ, Cerrada E and Laguna M. Gold(I) complexes with alkylated PTA (1,3,5-triaza-7-phosphaadamantane) phosphanes as anticancer metallodrugs. Eur. J. Med. Chem. (2014) 79: 164-72.
(24)      Dadkhah Aseman M, Nabavizadeh SM, Shahsavari HR and Rashidi M. C-H reductive elimination during the reaction of cycloplatinated(II) complexes with pyridine-2-thione: Kinetic follow up. RSC Adv. (2015) 5: 22692-702.
(25)      Fereidoonnezhad M, Niazi M, Ahmadipour Z, Mirzaee T, Faghih Z, Faghih Z and Shahsavari HR. Cyclometalated platinum(II) complexes comprising 2-(diphenylphosphino)pyridine and various thiolate ligands: Synthesis, spectroscopic characterization and biological activity. Eur. J. Inorg. Chem. (2017) 2247–54.
(26)      Niazi M, Shahsavari HR, Golbon Haghighi M, Halvagar MR, Hatami S and Notash B. Carbon-sulfur bond reductive coupling from a platinum(II) thiolate complex. RSC Adv. (2016) 6: 95073-84.
(27)      Raper ES. Complexes of heterocyclic thionates. Part 1. Complexes of monodentate and chelating ligands. Coord. Chem. Rev. (1996) 153: 199-255.
(28)      Dyadchenko VP, Belov NM, Lemenovskii DA, Antipin MY, Lyssenko KA, Bruce AE and Bruce MRM. Synthesis, crystal and molecular structure of gold(I) thiophenolate with 4′-ferrocenyl[1,1′]biphenylisocyanides. J. Organomet. Chem. (2010) 695: 304-9.
(29)      Römbke P, Schier A, Wiesbrock F, and Schmidbaur H. Gold(I) thiosulfonate complexes. Inorg. Chim. Acta (2003) 347: 123-8.
(30)      Schneider W, Bauer A and Schmidbaur H. (Isocyanide)gold(I) thiosalicylates:  supramolecular assembly based on both auriophilic and hydrogen bonding. Organometallics (1996) 15: 5445-6.
(31)      Dyadchenko VP, Belov NM, Dyadchenko MA, Slovokhotov YL, Banaru AM and Lemenovskii DA. A complex of gold(I) benzenethiolate with isocyanide: synthesis and crystal and molecular structures. Russ. Chem. Bull., Int. Ed. (2010) 59: 539-43.
(32)      Gutierrez A, Cativiela C, Laguna A and Gimeno MC. Bioactive gold(I) complexes with 4-mercaptoproline derivatives. Dalton Trans. (2016) 45: 13483-90.
(33)      Hokai Y, Jurkowicz B, Fernández-Gallardo J, Zakirkhodjaev N, Sanaú M, Muth TR and Contel M. Auranofin and related heterometallic gold(I)–thiolates as potent inhibitors of methicillin-resistant Staphylococcus aureus bacterial strains. J. Inorg. Biochem. (2014) 138: 81-8.
(34)      Dada O, Curran D, O'Beirne C, Müller-Bunz H, Zhu X and Tacke M. Synthesis and cytotoxicity studies of novel NHC–Gold(I) pseudohalides and thiolates. J. Organomet. Chem. (2017) 840: 30-7.
(35)      Chia EY, Naeem S, Delaude L, White AJP and Wilton-Ely JDET. Gold(i) complexes bearing mixed-donor ligands derived from N-heterocyclic carbenes. Dalton Trans. (2011) 40: 6645-58.
(36)      Mui YF, Fernández-Gallardo J, Elie BT, Gubran A, Maluenda I, Sanaú M, Navarro O and Contel Ma. Titanocene–Gold Complexes Containing N-heterocyclic carbene ligands inhibit growth of prostate, renal, and colon cancers in-vitro. Organometallics (2016) 35: 1218-27.
(37)      Bindoli A, Rigobello MP, Scutari G, Gabbiani C, Casini A and Messori L. Thioredoxin reductase: A target for gold compounds acting as potential anticancer drugs. Coord. Chem. Rev. (2009) 253: 1692-707.
(38)      Pia Rigobello M, Messori L, Marcon G, Agostina Cinellu M, Bragadin M, Folda A, Scutari G and Bindoli A. Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions. J. Inorg. Biochem. (2004) 98: 1634-41.
(39)      Serebryanskaya TV, Lyakhov AS, Ivashkevich LS, Schur J, Frias C, Prokop A and Ott I. Gold(i) thiotetrazolates as thioredoxin reductase inhibitors and antiproliferative agents. Dalton Trans. (2015) 44: 1161-9.
(40)      Gratteri P, Massai L, Michelucci E, Rigo R, Messori L, Cinellu MA, Musetti C, Sissi C and Bazzicalupi C. Interactions of selected gold(iii) complexes with DNA G quadruplexes. Dalton Trans. (2015) 44: 3633-9.
(41)      Marcon G, Carotti S, Coronnello M, Messori L, Mini E, Orioli P, Mazzei T, Cinellu MA and Minghetti G. Gold(III) complexes with bipyridyl ligands:  solution chemistry, cytotoxicity, and DNA binding properties. J. Med. Chem. (2002) 45: 1672-7.
(42)      Fereidoonnezhad M, Kaboudin B, Mirzaee T, Babadi Aghakhanpour R, Golbon Haghighi M, Faghih Z, Faghih Z, Ahmadipour Z, Notash B and Shahsavari HR. Cyclometalated platinum(II) complexes bearing bidentate O,O′-Di(alkyl)dithiophosphate ligands: photoluminescence and cytotoxic properties. Organometallics (2017) 36: 1707−17.
(43)      Fereidoonnezhad M, Niazi M, Shahmohammadi Beni M, Mohammadi S, Faghih Z, Faghih Z and Shahsavari HR. Synthesis, biological evaluation, and molecular docking studies on the DNA binding interactions of platinum(II) rollover complexes containing phosphorus donor ligands. ChemMedChem (2017) 12: 456-65.
(44)      Mojaddami A, Sakhteman A, Fereidoonnezhad M, Faghih Z, Najdian A, Khabnadideh S, Sadeghpour H and Rezaei Z. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies. Res. Pharm. Sci. (2017) 12: 21-30.
(45)      Zare S, Fereidoonnezhad M, Afshar D and Ramezani Z. A comparative QSAR analysis and molecular docking studies of phenyl piperidine derivatives as potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Comput. Biol. Chem. (2017) 67: 22-37.
(46)      Fereidoonnezhad M, Faghih Z, Mojaddami A, Tabaei SMH and Rezaei Z. Novel approach synthesis, molecular docking and cytotoxic activity evaluation of N-phenyl-2,2-dichloroacetamide derivatives as anticancer agents. J. Sci. Islam. Repub. Iran (2016) 27: 39-49.
(47)      Fereidoonnezhad M, Faghih Z, Mojaddami A, Sakhteman A and Rezaei Z. A comparative docking studies of dichloroacetate analogues on four isozymes of pyruvate dehydrogenase kinase in humans. Indian J. Pharm. Edu. Res. (2016) 50: S32-S8.
(48)      DeLano WL. Pymol: An open-source molecular graphics tool. CCP4 Newsletter On Protein Crystallography (2002) 40: 82-92.
(49)      Brandys MC, Jennings MC and Puddephatt RJ. Luminescent gold(I) macrocycles with diphosphine and 4,4'-bipyridyl ligands. J. Chem. Soc., Dalton Trans. (2000) 2000: 4601-6.
(50)      Hojoh K, Ohmiya H and Sawamura M. Synthesis of α-Quaternary formimides and aldehydes through umpolung asymmetric copper catalysis with isocyanides. J. Am. Chem. Soc. (2017) 139: 2184-7.
(51)      Zakrzewski J, Huras B and Kiełczewska A. Synthesis of isoselenocyanates. Synthesis (2016) 48: 85-96.
(52)      Fereidoonnezhad M, Shahsavari HR, Lotfi E, Babaghasabha M, Fakhri M, Faghih Z, Faghih Z and Hassan Beyzavi M. (Benzyl isocyanide) gold (I) pyrimidine‐2‐thiolate complex: Synthesis and biological activity. Appl. Organomet. Chem. (2018) 32: 1-7.
(53)      Zou T, Lum CT, Lok CN, Zhang JJ and Che CM. Chemical biology of anticancer gold(iii) and gold(i) complexes. Chem. Soc. Rev. (2015) 44: 8786-801.