, Volume 28, Issue 5, pp 845–860 | Cite as

Synthesis, characterization, cytotoxic and antitubercular activities of new gold(I) and gold(III) complexes containing ligands derived from carbohydrates

  • Joana Darc Souza Chaves
  • Jaqueline Lopes Damasceno
  • Marcela Cristina Ferreira Paula
  • Pollyanna Francielli de Oliveira
  • Gustavo Chevitarese Azevedo
  • Renato Camargo Matos
  • Maria Cristina S. Lourenço
  • Denise Crispim Tavares
  • Heveline Silva
  • Ana Paula Soares Fontes
  • Mauro Vieira de Almeida


Novel gold(I) and gold(III) complexes containing derivatives of d-galactose, d-ribose and d-glucono-1,5-lactone as ligands were synthesized and characterized by IR, 1H, and 13C NMR, high resolution mass spectra and cyclic voltammetry. The compounds were evaluated in vitro for their cytotoxicity against three types of tumor cells: cervical carcinoma (HeLa) breast adenocarcinoma (MCF-7) and glioblastoma (MO59J) and one non-tumor cell line: human lung fibroblasts (GM07492A). Their antitubercular activity was evaluated as well expressed as the minimum inhibitory concentration (MIC90) in μg/mL. In general, the gold(I) complexes were more active than gold(III) complexes, for example, the gold(I) complex (1) was about 8.8 times and 7.6 times more cytotoxic than gold(III) complex (8) in MO59J and MCF-7 cells, respectively. Ribose and alkyl phosphine derivative complexes were more active than galactose and aryl phosphine complexes. The presence of a thiazolidine ring did not improve the cytotoxicity. The study of the cytotoxic activity revealed effective antitumor activities for the gold(I) complexes, being more active than cisplatin in all the tested tumor cell lines. Gold(I) compounds (1), (2), (3), (4) and (6) exhibited relevant antitubercular activity even when compared with first line drugs such as rifampicin.


Gold complexes Carbohydrates Cytotoxic activity Antitubercular activity 





Nuclear magnetic resonance






Dimethyl formamide


4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)


High-resolution mass spectra (eletrospray ionization)


Nutrient mixture F-10


Dulbecco’s modified Eagle’s medium






Phosphate buffer saline



The authors thank FAPEMIG, CAPES and CNPq for financial support. This work is a collaboration research project of members of the Rede Mineira de Química (RQ-MG) supported by FAPEMIG (Project: CEX—RED-0010-14).


  1. Al-Jaroudi S, Monim-ul-Mehboob M, Altaf M, Al-Saadi AA, Wazeer MIM, Altuwaijri S, Isab AA (2014) Synthesis, spectroscopic characterization, electrochemical behavior and computational analysis of mixed diamine ligand gold(III) complexes: antiproliferative and in vitro cytotoxic evaluations against human cancer cell lines. Biometals 27:1115–1136CrossRefPubMedGoogle Scholar
  2. Al-Maythalony BA, Wazeer MIM, Isab AA (2009) Synthesis and characterization of gold(III) complexes with alkyldiamine ligands. Inorg Chim Acta 362:3109–3113CrossRefGoogle Scholar
  3. Almeida MV, Cesar ET, Fontes APS, Felício ECA (2000) Synthesis of platinum complexes from sugar derivatives. J Carbohydr Chem 19:323–329CrossRefGoogle Scholar
  4. Al-Thebeiti MS (1999) Regiocontrolled incorporation and annulation of glucose into spirothiazole and spirothiazoloxazole derivatives. J Carbohydr Chem 18:667–674CrossRefGoogle Scholar
  5. Amarante GW (2005) Síntese de Compostos Anfifílicos derivados da d-Galactose, Potenciais Agentes Surfactantes. Dissertação, Universidade Federal de Juiz de ForaGoogle Scholar
  6. Baenziger NC, Bennet WE, Soboroff DM (1976) Chloro(triphenylphosphine)god(I). Acta Cryst B 32:962CrossRefGoogle Scholar
  7. Barnard PJ, Berners-Price SJ (2007) Targeting the mitochondrial cell death pathway with gold compounds. Coord Chem Rev 251:1889–1902CrossRefGoogle Scholar
  8. Benedek TG (2004) The history of gold therapy for tuberculosis. J Hist Med Allied Sci 59:50–89CrossRefPubMedGoogle Scholar
  9. Brown FC (1961) 4-Thiazolidinones. Chem Rev 61:464–521CrossRefGoogle Scholar
  10. Bruni B, Guerri A, Marcon G, Messori L, Orioli P (1999) Structure and cytotoxic properties of some selected gold(III) complexes. Croat Chem Acta 72:221–229Google Scholar
  11. Canetti J, Rist E, Grosset R (1963) Measurement of sensitivity of the tuberculous bacillus to antibacillary drugs by the method of proportions. Methodology, resistance criteria, results and interpretation. Rev Tuberc Pneumol 27:217–272Google Scholar
  12. Casseta MI, Marzo T, Fallani S, Novelli A, Messori L (2014) Drug repositioning: auranofin as a prospective antimicrobial agent for the treatment of severe staphylococcal infections. Biometals 27:787–791CrossRefGoogle Scholar
  13. Chaves JDS, Neumann F, Francisco TM, Corrêa CC, Lopes MTP, Silva H, Fontes APS, Almeida MV (2014) Synthesis and cytotoxic activity of god(I) complexes containing phosphines and 3-benzyl-1,3-thiazolidine-2-thione or 5-phenyl-1,3,4-oxadiazole-2-thione as ligands. Inorg Chim Acta 414:85–90CrossRefGoogle Scholar
  14. Chen H, Jiao L, Guo Z, Li X, Ba C, Zhang J (2008) Synthesis and biological activity of novel thiazolidin-4-ones with a carbohydrate moiety. Carbohydr Res 343:3015–3020CrossRefPubMedGoogle Scholar
  15. Chirullo B, Sgarbanti R, Limongi D, Shytaj IL, Alvarez D, Das B, Boe A, Da Fonseca S, Chomont N, Liotta L, Petricoin E III, Norelli S, Pelosi E, Garaci E, Savarino A, Palamara AT (2013) A candidate anti-HIV reservoir compound, auranofin, exerts a selective ‘anti-memory’ effect by exploiting the baseline oxidative status of lymphocytes. Cell Death Dis 4:1–12CrossRefGoogle Scholar
  16. Coates GE, Kowala C, Swan JM (1966) Coordination compounds of Group IB metals. I. Triethylphosphine complexes of gold(I) mercaptides. Aust J Chem 19:539–545CrossRefGoogle Scholar
  17. Cuin A, Massabni AC, Pereira GA, Leite CQF, Pavan FR, Sesti-Costa R, Heinrich TA, Costa-Neto CM (2011) 6-Mercaptopurine complexes with silver and gold ions: anti-tuberculosis and anti-cancer activities. Biomed Pharmacother 65:334–338CrossRefPubMedGoogle Scholar
  18. Debnath A, Parsonage D, Andrade RM, He C, Cobo ER, Hirata K, Chen S, Rivera-García G, Orozco E, Martínez M, Guntilleke S, Barrios AM, Arkin MR, Poole LB, Mckerrow JH, Reed S (2012) A high throughput drug screen for Entamoeba histolytica identifies a new lead and target. Nat Med 18:956–960PubMedCentralCrossRefPubMedGoogle Scholar
  19. Delaunay D, Toupet L, Le Corre M (1995) Reactivity of/β-amino alcohols with carbon disulfide. Study on the synthesis of 2-oxazolidinethiones and 2-thiazolidinethiones. J Org Chem 60:6604–6607CrossRefGoogle Scholar
  20. Eisler R (2003) Chrysotherapy: a synoptic review. Inflamm Res 52:487–501CrossRefPubMedGoogle Scholar
  21. Eiter LC, Hall NW, Day CS, Saluta G, Kucera GL, Bierbach U (2009) Gold(I) analogues of a platinum-acridine antitumor agent are only moderately cytotoxic bus show potent activity against Mycobacterium tuberculosis. J Med Chem 52:6519–6522PubMedCentralCrossRefPubMedGoogle Scholar
  22. Franzblau SG, Witzig RS, McLaughlin JC, Torres P, Madico G, Hernandez A, Degnan MT, Cook MB, Quenzer VK, Fergu-son RM, Gilman RH (1998) Rapid, low-technology MIC determination with clinical Mycobacterium tuberculosis isolates by using the microplate Alamar Blue Assay. J Clin Microbiol 36:362–366PubMedCentralPubMedGoogle Scholar
  23. Gabbiani C, Casini A, Messori L (2007) Gold(III) compounds as anticancer drugs. Gold Bull 40:73–81CrossRefGoogle Scholar
  24. Garegg PJ (1984) Some aspects of régio-stereo-, and chemoselective reactions in carbohydrate chemistry. Pure Appl Chem 56:845–858CrossRefGoogle Scholar
  25. Gyepes A, Schaffer R, Bajor G, Woller A, Fodor P (2008) Synthesis and chromatographic study of methyl-2,3-O-isopropylidene-5-dimethyl-arsinoyl-β-d-ribofuranoside and methyl-2,3-O-isopropylidene-5-deoxy-5-dimethyl-thioarsinoyl-β-d-ribofuranoside. Polyhedron 27:2655–2661CrossRefGoogle Scholar
  26. Hickey JL, Ruhayel RA, Barnard PJ, Baker MV, Berners-Price SJ, Filipovska A (2008) Mitochondria-targeted chemotherapeutics: the rational design of gold(I) N-heterocyclic carbene complexes that are selectively toxic to cancer cells and target protein selenols in preference to thiols. J Am Chem Soc 130:12570–12571CrossRefPubMedGoogle Scholar
  27. Ingles DL, Whistler RL (1962) Preparation of several methyl d-pentothiapyranosides. J Org Chem 27:3896–3898CrossRefGoogle Scholar
  28. Lessa JA, Ferraz KSO, Guerra JC, De Miranda LF, Romeiro CFD, Souza-Fagundes EM, Barbeira PJS, Beraldo H (2012) Spectroscopic and electrochemical characterization of gold(I) and gold(III) complexes with glyoxaldehyde bis(thiosemicarbazones): cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity. Biometals 25:587–598CrossRefPubMedGoogle Scholar
  29. Maiore L, Cinellu MA, Nobili S, Landini I, Mini E, Gabbiani C, Messori L (2012) Gold(III) complexes with 2-substituted pyridines as experimental anticancer agents: solution behavior, reactions with model proteins, antiproliferative properties. J Inorg Biochem 108:123–127CrossRefPubMedGoogle Scholar
  30. Messori L, Marcon G (2004) Gold complexes as antitumor agents. Met Ions Biol 42:385–424Google Scholar
  31. Messori L, Francesco A, Marcon G, Orioli P, Fontani M, Mini E, Mazzei T, Carott S, O’connell T, Zanello P (2000) Gold(III) complexes as potential antitumor agents: solution chemistry and cytotoxic properties of some selected gold(III) compounds. J Med Chem 43:3541–3548CrossRefPubMedGoogle Scholar
  32. Mirabelli CK, Johson RK, Sung CM, Faucette L, Muirhead K, Crooke ST (1985) Models cytotoxic properties of auranofin, a coordinated gold in vitro antitumor activity and in vivo evaluation. Cancer Res 45:32–39PubMedGoogle Scholar
  33. Mirabelli CK, Johson RK, Hill DT, Faucette L, Girard GR, Kuo GY, Sung CM, Crooke ST (1986) Correlation of the in vitro cytotoxic and in vivo antitumor activities of gold(I) coordination complexes. J Med Chem 29:218–223CrossRefPubMedGoogle Scholar
  34. Navarro M (2009) Gold complexes as potential anti-parasitic agentes. Coord Chem Rev 253:1619–1626CrossRefGoogle Scholar
  35. Ott I (2009) On the medicinal chemistry of gold complexes as anticancer drugs. Coord Chem Rev 253:1670–1681CrossRefGoogle Scholar
  36. Ott I, Qian X, Xu Y, Vlecken DHW, Marques IJ, Kubutat D, Sheldrick WS, Jesse P, Prokop A, Bagowski CP (2009) A gold(I) phosphine complex containing a naphthalimide ligand functions as a TrxR inhibiting antiproliferative agent and angiogenesis inhibitor. J Med Chem 52:763–770CrossRefPubMedGoogle Scholar
  37. Rauter AP, Padilha M, Figueiredo JA, Ismael MI, Justino J, Ferreira H, Ferreira MJ, Rajendran C, Wilkins R, Vaz PD, Calhorda MJJ (2005) Bioactive pseudo-C-nucleosides containing thiazole, theazolidinone, and tetrazole rings. Carbohydr Chem 24:275–296CrossRefGoogle Scholar
  38. Reis RS, Ijr Neves, Lourenço SLS, Fonseca LS, Lourenço MCS (2004) Comparison of flow cytometric and Alamar Blue Tests with the proportional method for testing susceptibility of Mycobacterium tuberculosis to rifampin and isoniazid. Clin Microbiol 42:2247–2248CrossRefGoogle Scholar
  39. Releling H, Rouville E, Chittenden GJF (1987) The chemistry of d-gluconic acid derivatives. Part 1. Synthesis of 3,4;5,6-di-O-isopropylidene-d-glucitol and 2,3;4,5-di-O-isopropylidene-aldehydo-d-arabinose from d-glucono-1,5-lactone. Rec Trav Chim Pays-Bas 106:461–464CrossRefGoogle Scholar
  40. Rigobello MP, Messori L, Marcon G, Bragadin M, Folda A, Scutari G, Bindoli A (2004) Gold complexes inhibit mitochondrial thioredoxin reductase: consequences on mitochondrial functions. J Inorg Biochem 98:1634–1641CrossRefPubMedGoogle Scholar
  41. Sadler PJ, Nasr M, Narayanan VL (1984) In: Douple EB, Krakhoff IH, Hacker MP (eds) Platinum coordination complexes in cancer chemotherapy. Martinus Nijhoff Publishers, Boston, pp 290–304CrossRefGoogle Scholar
  42. Shi J-C, Chen L-J, Huang S-Y, Wu D-X, Kang B-S (1997) Chiral phosphine ligands derived from sugars 10. Syntheses, structure, characterization and activity of the gold(I) complexes with sugar-substructure phosphine ligands. J Organomet Chem 535:17–23CrossRefGoogle Scholar
  43. Shoeib T, Atkinson DW, Sharp BL (2010) Structural analysis of the anti-arthritic drug Auranofin: its complexes with cysteine, selenocysteine and their fragmentation products. Inorg Chim Acta 363:184–192CrossRefGoogle Scholar
  44. Simon TM, Kunishima DH, Vibert GJ, Lorber A (1979) Inhibitory effects of a new oral gold compound on hela cells. Cancer 44:1965–1975CrossRefPubMedGoogle Scholar
  45. Simon TM, Kunishima DH, Vibert GJ, Lorber A (1981) Screening trial with the coordinated gold compound auranofin using mouse lymphocytic leukemia P3881. Cancer Res 41:94–97PubMedGoogle Scholar
  46. Sout EI, Doane WM, Russell CR, Jones LB (1975) Photolysis of some carbohydrate dithiobis(thioformates). J Org Chem 40:1331–1336CrossRefGoogle Scholar
  47. Sun RW-Y, Che C-M (2009) The anti-cancer properties of gold(III) compounds with dianionic porphyrin and tetradentate ligands. Coord Chem Rev 253:1682–1691CrossRefGoogle Scholar
  48. Tiekink ERT (2002) Gold derivatives for the treatment of cancer. Crit Ver Oncol Hematol 42:225–248CrossRefGoogle Scholar
  49. Trávnicek Z, Starha P, Vanco J, Hosek SJ, Suchý PJ, Prazanová G (2012) Anti-inflammatory active gold(I) complexes involving 6-substituted-purine derivatives. J Med Chem 55:4568–4579CrossRefPubMedGoogle Scholar
  50. Tsubomura T, Yano S, Kobayashi K, Sakurai T, Yoshikawa S (1986) First synthesis and characterization of platinum(II) complexes of amino sugars having anti-tumour activity; crystal structure of [ptcl2(methyl 2,3-dideoxy-α-d-mannopyranoside)] H2O. J Chem Soc Chem Commun 6:459–460CrossRefGoogle Scholar
  51. Vanitha JD, Paramasivan CN (2004) Evaluation of microplate Alamar blue assay for drug susceptibility testing of Mycobacterium avium complex isolates. Diagn Microbiol Infect Dis 49:179–180CrossRefPubMedGoogle Scholar
  52. Yoshida S-I, Kato T, Sakurada S, Kurono C, Yang J-P, Matsui N, Soji T, Okamato T (1999) Inhibition of IL-6 and IL-8 induction from cultured rheumatoid synovial fibroblasts by treatment with aurothioglucose. Int Immunol 11:151–158CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Joana Darc Souza Chaves
    • 1
  • Jaqueline Lopes Damasceno
    • 2
  • Marcela Cristina Ferreira Paula
    • 2
  • Pollyanna Francielli de Oliveira
    • 2
  • Gustavo Chevitarese Azevedo
    • 1
  • Renato Camargo Matos
    • 1
  • Maria Cristina S. Lourenço
    • 3
  • Denise Crispim Tavares
    • 2
  • Heveline Silva
    • 1
  • Ana Paula Soares Fontes
    • 1
  • Mauro Vieira de Almeida
    • 1
  1. 1.Departamento de Química, ICEUniversidade Federal de Juiz de ForaJuiz de ForaBrazil
  2. 2.Departamento de Pesquisas com Produtos NaturaisUniversidade de FrancaFrancaBrazil
  3. 3.Instituto de Tecnologia em Fármacos-Far ManguinhosFundação Oswaldo CruzRio de JaneiroBrazil

Personalised recommendations