Gold Bulletin

, Volume 52, Issue 1, pp 35–50 | Cite as

Three new dicyanidoaurate(I)-based complexes exhibiting significant antiproliferative property: synthesis and characterization

  • Ali Aydın
  • Ahmet KaradağEmail author
  • Şaban Tekin
  • Hüseyin Akbaş
Original Paper


The Au(CN)2 ion and its metal-ligand compounds have recently gained considerable interest in industrial applications such as optical diagnostics systems as well as pharmacology with antirheumatic and antitumor activity. Here, [Ni2(N-bishydeten)2][Au(μ-CN)2]3[Au(CN)2]·H2O (C1), [Cu2(N-bishydeten)2][Au(μ-CN)2]3[Au(CN)2]·H2O (C2), and [Zn2(μ-N-bishydetenH)(N-bishydeten)(NC)2Au][Au(CN)2] (C3) were synthesized by reaction of the metal salts with N,N-bis(2-hydroxyethyl)ethylenediamine (N-bisyhdeten) and K[Au(CN)2]. The Au(I) compounds were characterized using elemental analysis and FT-IR. ESI-MS and thermal measurement techniques and their pharmacological properties were also tested. The DNA/bovine serum albumin (BSA) interactions of these compounds were demonstrated by spectrophotometric titration, fluorometric ethidium bromide kinetics, and DNA electrophoresis studies, and the stability of these compounds in physiological solution was also determined. The findings indicate that these compounds displayed a DNA/BSA-binding activity similar to that of cisplatin and exhibited a strong aqueous stability. The Au(I) compounds were potent antiproliferative agents with low necrotic activity and exhibited dose-dependent growth inhibition of cancer cells with IC50 value of 0.12–0.73 μM. Accumulation of p53 and decrease in Bcl-2 in cells exposed to Au(I) compounds may be the main causes for apoptotic effects, such as DNA fragmentation and nuclear collapse. Investigations regarding the mode of action of Au(I) compounds on cells revealed that they reduce the cell migration rate and the level of cytoskeletal proteins, namely CK7 and CK20. On the basis of this evidence, we suggest that strong antiproliferative activity, low necrotic effect, and micromolar dose range observed for Au(I) compounds make them suitable candidates for further pharmacological evaluation as chemotherapeutic agents in colon and cervix cancer.


N,N-bis(2-hydroxyethyl)ethylenediamine Dicyanidoaurate(I) Coordination compounds Antiproliferative activity Apoptosis 


Supplementary material

13404_2018_251_MOESM1_ESM.docx (2 mb)
ESM 1 (DOCX 2003 kb)


  1. 1.
    Medici S, Peana M, Nurchi VM, Lachowicz JI, Crisponi G, Zoroddu MA (2015) Noble metals in medicine: latest advances. Coord Chem Rev 284:329–350. Google Scholar
  2. 2.
    Barry NPE, Sadler PJ (2013) Exploration of the medical periodic table: towards new targets. Chem Commun 49:5106–5131. Google Scholar
  3. 3.
    Madeira JM, Gibson DL, Kean WF, Klegeris A (2012) The biological activity of auranofin: implications for novel treatment of diseases. Inflammopharmacol 20:297–306. Google Scholar
  4. 4.
    Nardon C, Boscutti G, Fregona D (2014) Beyond platinums: gold complexes as anticancer agents. Anticancer Res 34:487–492Google Scholar
  5. 5.
    Ndagi U, Mhlongo N, Soliman ME (2017) Metal complexes in cancer therapy—an update from drug design perspective. Dovepress 11:599–616. Google Scholar
  6. 6.
    Allardyce CS, Dyson PJ (2016) Metal-based drugs that break the rules. Dalton Trans 45:3201–3209. Google Scholar
  7. 7.
    Endrizzi F, Di Bernardo P, Zanonato PL, Tisato F, Porchia M, Isse AA, Melchior A, Tolazzi M (2017) Cu(I) and Ag(I) complex formation with the hydrophilic phosphine 1,3,5-triaza-7-phosphadamantane in different ionic media. How to estimate the effect of a complexing medium. Dalton Trans 46:1455–1466. Google Scholar
  8. 8.
    Ellahioui Y, Prashar S, Gómez-Ruiz S (2017) Anticancer applications and recent investigations of Metallodrugs based on gallium, tin and titanium. Inorganics 5:4. Google Scholar
  9. 9.
    Muggia FM, Bonetti A, Hoeschele JD, Rozencweig M, Howell SB (2015) Platinum antitumor complexes: 50 years since Barnett Rosenberg’s discovery. J Clin Oncol 33(35):4219–4226. Google Scholar
  10. 10.
    Deo KM, Pages BJ, Ang DL, Gordon CP, Aldrich-Wright JR (2016) Transition metal intercalators as anticancer agents-recent advances. Int J Mol Sci 17:1818. Google Scholar
  11. 11.
    Rackham O, Nichols SJ, Leedman PJ, Berners-Price SJ, Filipovska A (2007) A gold(I) phosphine complex selectively induces apoptosis in breast cancer cells: implications for anticancer therapeutics targeted to mitochondria. Biochem Pharmacol 74:992–1002. Google Scholar
  12. 12.
    Liu JJ, Galettis P, Farr A, Maharaj L, Samarasinha H, McGechan AC, Baguley BC, Bowen RJ, Berners-Price SJ, McKeage MJ (2008) In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake. J Inorg Biochem 102:303–310. Google Scholar
  13. 13.
    Yan JJ, Chow AL-F, Leung C-H, Sun RW-Y, Ma D-L, Che C-M (2010) Cyclometalated gold(III) complexes with N-heterocyclic carbene ligands as topoisomerase I poisons. Chem Commun 46:3893–3895. Google Scholar
  14. 14.
    Schilling T, Keppler KB, Heim ME, Niebch G, Dietzfelbinger H, Rastetter J, HanauskeInvest A-R (1995) Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane. New Drugs 13:327–332. Google Scholar
  15. 15.
    Roder C, Thomson MJ (2015) Auranofin: repurposing an old drug for a golden new age. Drugs R D 15:13–20. Google Scholar
  16. 16.
    Chitambar CR (2012) Gallium-containing anticancer compounds. Future Med Chem 4:1257–1272. Google Scholar
  17. 17.
    Egger AE, Rappel C, Jakupec MA, Hartinger CG, Heffeter F, Keppler BK (2009) Development of an experimental protocol for uptake studies of metal compounds in adherent tumor cells. J Anal At Spectrom 24:51–61. Google Scholar
  18. 18.
    Leznoff DB, Lefebvre J (2005) Coordination polymers with cyanoaurate building blocks: potential new industrial applications for gold. Gold Bull 38:47–54. Google Scholar
  19. 19.
    Muňoz MC, Real JA (2011) Thermo-, piezo-, photo- and chemo-switchable spin crossover iron(II)-metallocyanate based coordination polymers. Coord Chem Rev 255:2068–2093. Google Scholar
  20. 20.
    Paraschiv C, Andruh M, Ferlay S, Hosseini MW, Kyritsakas N, Planeix JM, Stanica N (2005) Alkoxo-bridged copper(II) complexes as nodes in designing solid-state architectures. The interplay of coordinative and d10–d10 metal–metal interactions in sustaining supramolecular solid-state architectures. Dalton Trans 0:1195–1202. Google Scholar
  21. 21.
    Shorrock CJ, Jong H, Batchelor RJ, Leznoff DB (2003) [Au(CN)4] as a supramolecular building block for heterobimetallic coordination polymers. Inorg Chem 42:3917–3924. Google Scholar
  22. 22.
    Suárez-Varela J, Mota AJ, Aouryaghal H, Cano J, Rodríguez-Diéguez A, Luneau D, Colacio E (2008) Anion influence on the structure and magnetic properties of a series of multidimensional pyrimidine-2-carboxylato-bridged copper(II) complexes. Inorg Chem 47:8143–8158. Google Scholar
  23. 23.
    Deák A, Tunyogi T, Jobbágy C, Károly Z, Baranyai P, Pálinkás G (2012) Cyanide-bridged bimetallic multidimensional structures derived from organotin(IV) and dicyanoaurate building blocks:ion exchange, luminescence, and gas sorption properties. Gold Bull 45:35–41. Google Scholar
  24. 24.
    Katz MJ, Ramnial T, Yu HZ, Leznoff DB (2008) Polymorphism of Zn[Au(CN)2]2 and its luminescent sensory response to NH3 vapor. J Am Chem Soc 130:10662–10673. Google Scholar
  25. 25.
    Amo-Ochoa P, Delgado S, Gallego A, Gómez-García CJ, Jiménez-Aparicio R, Martínez G, Perles J, Torres MR (2012) Structure and properties of one-dimensional heterobimetallic polymers containing dicyanoaurate and dirhodium(II) fragments. Inorg Chem 51:5844–5849. Google Scholar
  26. 26.
    Karadağ A, Aydın A, Dede S, Tekin Ş, Yanar Y, Çadırcı BH, Soylu MS, Andaç Ö (2015) Five novel dicyanidoaurate (I)-based complexes exhibiting significant biological activities: synthesis, characterization and three crystal structures. New J Chem 39:8136–8152. Google Scholar
  27. 27.
    Karadağ A, Aydın A, Özdemir A, Tekin Ş (2014) Antiproliferative and cytotoxic activities of a new cyanido coordination compound on several cancer cell lines. J Biotechnol 185:105. Google Scholar
  28. 28.
    Tekin Ş, Aydın A, Dede S, Karadağ A (2014) Antiproliferative activity of a new coordination compound containing AuI(CN)2 in some cancer cell lines. J Biotechnol 185:28–29. Google Scholar
  29. 29.
    Korkmaz N, Karadağ A, Aydın A, Yanar Y, Karaman İ, Tekin Ş (2014) Synthesis and characterization of two novel dicyanidoargentate (I) complexes containing N-(2-hydroxyethyl) ethylenediamine exhibiting significant biological activity. New J Chem 38:4760–4773. Google Scholar
  30. 30.
    Korkmaz N, Aydın A, Akbaş H, Yerli Y, Tekin Ş, Karadağ A (2017) Complexes with significant anticancer and antibacterial properties containing silver(I)-centered components: a novel sandwich-type like polymeric structure. Inorg Chem submittedGoogle Scholar
  31. 31.
    Korkmaz N, Aydın A, Karadağ A, Yanar Y, Maaşoğlu Y, Şahin E, Tekin Ş (2017) New bimetallic dicyanidoargentate(I)-based coordination compounds: synthesis, characterization, biological activities and DNA-BSA binding affinities. Spectrochim Acta Part A: Mol Biomol Spect 173:1007–1022. Google Scholar
  32. 32.
    Ćernák J, Orendáč M, Potočňák I, Chomič J, Orendáčová A, Skoršepa J, Feher A (2002) Cyanocomplexes with one-dimensional structures: preparations, crystal structures and magnetic properties. Coord Chem Rev 224:51–66. Google Scholar
  33. 33.
    Gong JP, Traganos F, Darzynkiewicz Z (1994) A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem 218:314–319. Google Scholar
  34. 34.
    Ghotbi MY (2010) Synthesis and characterization of nano-sized ε-Zn(OH)2 and its decomposed product, nano-zinc oxide. J Alloys Compd 491:420–422. Google Scholar
  35. 35.
    Sharma PK, Dutta RK, Kumar M, Singh PK, Pandey AC (2009) Luminescence studies and formation mechanism of symmetrically dispersed ZnO quantum dots embedded in SiO2 matrix. J Luminescence 129:605–610. Google Scholar
  36. 36.
    Song B, Reuber J, Ochs C, Hahn FE, Lügger T, Orvig C (2001) Effects of sequential replacement of -NH2 by -OH in the tripodal tetraamine tren on its acidity and metal ion coordinating properties. Inorg Chem 40:1527–1535. Google Scholar
  37. 37.
    Nakamato K (2009) Infrared and raman spectra of inorganic and coordination compounds. Wiley Interscience: John Wiley & Sons Inc, HobokenGoogle Scholar
  38. 38.
    Şenocak A, Karadağ A, Şahin E, Yerli Y (2011) Synthesis and characterization of new metal–organic frameworks based on tetracyanoplatinate (II) and N,N′-bis (2-hydroxyethyl) ethylenediamine: single crystal structures of ZnII and CdII complexes along with magnetic properties of NiII and CuII complexes. J Inorg Organomet Polym 21:438–449. Google Scholar
  39. 39.
    Korkmaz ŞA, Karadağ A, Yerli Y, Soylu MS (2014) Synthesis and characterization of new heterometallic cyanido complexes based on [Co(CN)6]3-building blocks: crystal structure of [Cu2(N-bishydeten)2Co(CN)6]·3H2O having a strong antiferromagnetic exchange. New J Chem 38:5402–5410. Google Scholar
  40. 40.
    Korkmaz ŞA, Karadağ A, Aydın A, Yerli Y, Soylu MS (2016) Binuclear cyanido complexes containing [Pt(CN)4]2- building block: synthesis, crystal structures, magnetic properties and anticancer activities. Inorg Chim Acta 453:154–168. Google Scholar
  41. 41.
    Korkmaz ŞA, Karadağ A, Korkmaz N, Andaç Ö, Gürbüz N, Özdemir İ, Topkaya R (2013) Five complexes containing N,N-bis(2-hydroxyethyl) ethylenediamine with tetracyanidopalladate(II): synthesis, crystal structures, thermal, magnetic, and catalytic properties. J Coord Chem 66:3072–3091. Google Scholar
  42. 42.
    Aydın A, Karadağ A, Tekin Ş, Korkmaz N, Özdemir A (2015) Two new coordination polymers containing dicyanidoargentate(I) and dicyanidoaurate(I): synthesis and characterization, and a detailed in vitro investigation of their anticancer activities on some cancer cell lines. Turk J Chem 39:532–549. Google Scholar
  43. 43.
    Aydın A, Korkmaz N, Tekin Ş, Karadağ A (2014) Anticancer activities and mechanism of action of 2 novel metal complexes, C16H34N8O5Ag2Cd and C11H16N7O2Ag3Ni. Turk J Biol 38:948–955. Google Scholar
  44. 44.
    Isab AA, Shaikh MN, Monim-ul-Mehboob M, Al-Maythalony BA, Wazeer MIM, Altuwaijri S (2011) Synthesis, characterization and anti proliferative effect of [Au(en)2]Cl3 and [Au(N-propyl-en)2]Cl3 on human cancer cell lines. Spectrochim Acta Mol Biomol Spectrosc 79:1196–1201. Google Scholar
  45. 45.
    Pérez SA, de Haro C, Vicente C, Donaire A, Zamora A, Zajac J, Kostrhunova H, Brabec V, Bautista D, Ruiz J (2017) New Acridine Thiourea Gold(I) anticancer agents: targeting the nucleus and inhibiting vasculogenic mimicry. ACS Chem Biol 12:1524–1537. Google Scholar
  46. 46.
    Chiara N, Giulia B, Chiara G, Lara M, Nicolò P, Ambrogio F, Luigi M, Dolores F (2017) Cell and cell-free mechanistic studies on two Gold(III) complexes with proven antitumor properties. Eur J Inorg Chem 2017:1737–1744. Google Scholar
  47. 47.
    Muhammad A, Muhammad M, Abdel-Nasser K, Giuseppe C, Roberto L, Marcia O, Naike C, Marta C, Cinzia B, Zahid HS, Donatella A, Anvarhusein AI (2017) New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status. Oncotarget 8:490–505. Google Scholar
  48. 48.
    Altaf M, Monim-ul-Mehboob M, Isab AA, Dhuna V, Bhatia G, Dhuna K, Altuwaijri S (2015) The synthesis, spectroscopic characterization and anticancer activity of new mono and binuclear phosphanegold(I) dithiocarbamate complexes. New J Chem 39:377–385. Google Scholar
  49. 49.
    Newcombe S, Bobin M, Shrikhande A, Gallop C, Pace Y, Yong H, Gates R, Chaudhuri S, Roe M, Hoffmann E, Viseux EME (2013) Gold amides as anticancer drugs: synthesis and activity studies. Org Biomol Chem 11:3255–3261. Google Scholar
  50. 50.
    Vančo J, Gáliková J, Hošek J, Dvořák Z, Paráková L, Trávníček Z (2014) Gold(I) complexes of 9-Deazahypoxanthine as selective antitumor and anti-inflammatory agents. PLoS One 9:e109901. Google Scholar
  51. 51.
    To YF, Sun RW-Y, Chen Y, Chan VS-F, Yu W-Y, Tam PK-H, Che C-M, Lin C-LS (2009) Gold(III) porphyrin complex is more potent than cisplatin in inhibiting growth of nasopharyngeal carcinoma in vitro and in vivo. Int J Cancer 124:1971–1979. Google Scholar
  52. 52.
    Zhang J-J, Sun RW-Y, Che C-M (2012) A dual cytotoxic and anti-angiogenic water-soluble gold(III) complex induces endoplasmic reticulum damage in HeLa cells. Chem Commun 48:3388–3390. Google Scholar
  53. 53.
    Lupidi G, Avenali L, Bramucci M, Quassinti L, Pettinari R, Khalife HK, Gali-Muhtasib H, Marchetti F, Pettinari C (2013) Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells. J Inorg Biochem 124:78–87. Google Scholar
  54. 54.
    Cattaruzza L, Fregona D, Mongiat M, Ronconi L, Fassina A, Colombatti A, Aldinucci D (2011) Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. Int J Cancer 128:206–215. Google Scholar
  55. 55.
    Fernández-Gallardo J, Elie BT, Sadhukha T, Prabha S, Sanaú M, Rotenberg SA, Ramos JW, Contel M (2015) Heterometallic titanium–gold complexes inhibit renal cancer cells in vitro and in vivo. Chem Sci 6:5269–5283. Google Scholar
  56. 56.
    Bhatia M, McGrath KL, Di Trapani G, Charoentong P, Shah F, King MM, Clarke FM, Tonissen KF (2016) The thioredoxin system in breast cancer cell invasion and migration. Redox Biol 8:68–78. Google Scholar
  57. 57.
    Lum CT, Liu X, Sun RW, Li XP, Peng Y, He ML, Kung HF, Che CM, Lin MCM (2010) Gold(III) porphyrin 1a inhibited nasopharyngeal carcinoma metastasis in vivo and inhibited cell migration and invasion in vitro. Cancer Lett 294:159–166. Google Scholar
  58. 58.
    Wilson CR, Fagenson AM, Ruangpradit W, Muller MT, Munro OQ (2013) Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors. Inorg Chem 52:7889–7906. Google Scholar
  59. 59.
    Nandy A, Dey S, Das S, Munda R, Dinda J, Saha K (2014) Gold (I) N-heterocyclic carbene complex inhibits mouse melanoma growth by p53 upregulation. Mol Cancer 13:57. Google Scholar
  60. 60.
    Cheng X, Holenya P, Can S, Alborzinia H, Rubbiani R, Ott I, Wölfl S (2014) A TrxR inhibiting gold(I) NHC complex induces apoptosis through ASK1-p38-MAPK signaling in pancreatic cancer cells. Mol Cancer 13:221. Google Scholar
  61. 61.
    Sirajuddin M, Ali S, Badshah A (2013) Drug-DNA interactions and their study by UV–visible, fluorescence spectroscopies and cyclic voltammetry. J Photochem Photobiol B 124:1–19. Google Scholar
  62. 62.
    N'soukpoé-Kossi CN, Descôteaux C, Asselin E, Tajmir-Riahi H-A, Bérubé G (2008) DNA interaction with novel antitumor estradiol–platinum(II) hybrid molecule: a comparative study with cisplatin drug. DNA Cell Biol 27:101–107. Google Scholar
  63. 63.
    Jangir DK, Charak S, Mehrotra R, Kundu S (2011) FTIR and circular dichroism spectroscopic study of interaction of 5-fluorouracil with DNA. J Photochem Photobiol B 105:143–148. Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Faculty of Science, Department of BiotechnologyBartın UniversityBartınTurkey
  2. 2.Faculty of Art and Science, Department of ChemistryGaziosmanpaşa UniversityTokatTurkey
  3. 3.TÜBİTAK MRC Genetic Engineering & Biotechnology InstituteGebzeTurkey
  4. 4.Faculty of Medicine, Department of Basic Medical Sciences, Medical BiologyUniversity of Health SciencesIstanbulTurkey

Personalised recommendations