BioMetals

, Volume 29, Issue 3, pp 515–526 | Cite as

Metal complexes of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone: cytotoxic activity and investigation on the mode of action of the gold(III) complex

  • Luciana B. P. Sâmia
  • Gabrieli L. Parrilha
  • Jeferson G. Da Silva
  • Jonas P. Ramos
  • Elaine M. Souza-Fagundes
  • Silvia Castelli
  • Venn Vutey
  • Alessandro Desideri
  • Heloisa Beraldo
Article

Abstract

Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).

Graphical Abstract

Keywords

Chalcone Thiosemicarbazone Metal complexes Cytotoxic activities Thioredoxin reductase Topoisomerase IB 

References

  1. Andrade RM, Reed SL (2015) New drug target in protozoan parasites: the role of thioredoxin reductase. Front Microbiol 6:1–7. doi:10.3389/fmicb.2015.00975 CrossRefGoogle Scholar
  2. Baikar S, Malpathak N (2010) Secondary metabolites as DNA topoisomerase inhibitors: a new era towards designing of anticancer drugs. Pharmacogn Rev 4:12–26. doi:10.4103/0973-7847.65320 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Beraldo H, Gambino D (2004) The wide pharmacological versatility of semicarbazones, thiosemicarbazones and their metal complexes. Mini Rev Med Chem 4:31–39. doi:10.2174/1389557043487484 (and references therein)CrossRefPubMedGoogle Scholar
  4. Bratsos I, Jedner S, Gianferrara T, Alessio E (2007) Ruthenium anticancer compounds: challenges and expectations. Chimia 61:692–697. doi:10.2533/chimia.2007.692 CrossRefGoogle Scholar
  5. Castelli S, Vassallo O, Katkar P, Che CM, Sun RWY, Desideri A (2011) Inhibition of human DNA topoisomerase IB by a cyclometalated gold III compound: analysis on the different steps of the enzyme catalytic cycle. Arch Biochem Biophys 516:108–112. doi:10.1016/j.abb.2011.10.008 CrossRefPubMedGoogle Scholar
  6. Castelli S, Katkar P, Vassallo O, Falconi M, Linder S, Desideri A (2013) A natural anticancer agent thaspine targets human topoisomerase IB. Anti-Cancer Agents Med Chem 13:356–363. doi:10.2174/187152013804711128 CrossRefGoogle Scholar
  7. Cervantes G, Moreno V, Molins E, Quirós M (1998) Pd(II) and Pt(II) D-penicillamine complexes. Crystal structure of a tridentate d-penicillamine cluster of Pd(II). Polyhedron 17:3343–3350. doi:10.1016/S0277-5387(98)00114-4 CrossRefGoogle Scholar
  8. Che CM, Siu FM (2010) Metal complexes in medicine with a focus on enzyme inhibition. Curr Opin Chem Biol 14:255–261. doi:10.1016/j.cbpa.2009.11.015 CrossRefPubMedGoogle Scholar
  9. Chillemi G, Fiorani P, Castelli S, Bruselles A, Benedetti P, Desideri A (2005) Effect on DNA relaxation of the single Thr718Ala mutation in human topoisomerase I: a functional and molecular dynamics study. Nucleic Acids Res 33:3339–3350. doi:10.1093/nar/gki642 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Colotti G, Ilari A, Boffi A, Morea V (2013) Metals and metal derivatives in medicine. Mini-Rev Med Chem 13:211–221. doi:10.2174/138955713804805238 PubMedGoogle Scholar
  11. Da Silva JG, Perdigão CCH, Speziali NL, Beraldo H (2013a) Chalcone-derived thiosemicarbazones and their zinc(II) and gallium(III) complexes: spectral studies and antimicrobial activity. J Coord Chem 66:385–401. doi:10.1080/00958972.2012.757762 CrossRefGoogle Scholar
  12. Da Silva JG, Despaigne AAR, Louro SRW, Bandeira CC, Souza-Fagundes EM, Beraldo H (2013b) Cytotoxic activity, albumin and DNA binding of new copper(II) complexes with chalcone-derived thiosemicarbazones. Eur J Med Chem 65:415–426. doi:10.1016/j.ejmech.2013.04.036 CrossRefPubMedGoogle Scholar
  13. De Oliveira KN, Andermark V, von Grafenstein S, Onambele LA, Dahl G, Rubbiani R, Wolber G, Gabbiani C, Messori L, Prokop A, Ott I (2013) Butyltin(IV) benzoates: inhibition of thioredoxin reductase, tumor cell growth inhibition, and interactions with proteins. ChemMedChem 8:256–264. doi:10.1002/cmdc.201200505 CrossRefGoogle Scholar
  14. Dimmock JR, Elias DW, Beazely MA, Kandepu NM (1999) Bioactivities of chalcones. Curr Med Chem 6:1125–1149PubMedGoogle Scholar
  15. Ferraz KSO, Ferandes L, Carrilho D, Pinto MCX, Leite MF, Souza-Fagundes EM, Speziali NL, Mendes IC, Beraldo H (2009) 2-Benzoylpyridine-N(4)-tolyl thiosemicarbazones and their palladium(II) complexes: cytotoxicity against leukemia cells. Bioorg Med Chem 17:7138–7144. doi:10.1016/j.bmc.2009.08.063 CrossRefPubMedGoogle Scholar
  16. Ferraz KOS, Cardoso GMM, Bertollo CM, Souza-Fagundes EM, Speziali N, Zani CL, Mendes IC, Gomes MA, Beraldo H (2011) N(4)-tolyl-2-benzoylpyridine-derived thiosemicarbazones and their palladium(II) and platinum(II) complexes: cytotoxicity against human solid tumor cells. Polyhedron 30:315–321. doi:10.1016/j.poly.2010.10.014 CrossRefGoogle Scholar
  17. Ferraz KSO, Silva NF, Da Silva JG, Speziali NL, Mendes IC, Beraldo H (2012) Structural studies on acetophenone- and benzophenone-derived thiosemicarbazones and their zinc(II) complexes. J Mol Struct 1008:102–107. doi:10.1016/j.molstruc.2011.11.035 CrossRefGoogle Scholar
  18. Ferraz KSO, Reis DC, Da Silva JG, Souza-Fagundes EM, Baran EJ, Beraldo H (2013a) Investigation on the bioactivities of clioquinol and its bismuth(III) and platinum(II, IV) complexes. Polyhedron 63:28–35. doi:10.1016/j.poly.2013.07.008 CrossRefGoogle Scholar
  19. Ferraz KSO, Da Silva JG, Costa FM, Mendes BM, Rodrigues BL, dos Santos RG, Beraldo H (2013b) N(4)-Tolyl-2-acetylpyridine thiosemicarbazones and their platinum(II, IV) and gold(III) complexes: cytotoxicity against human glioma cells and studies on the mode of action. Biometals 26:677–691. doi:10.1007/s10534-013-9639-x CrossRefPubMedGoogle Scholar
  20. Garbutcheon-Singh KB, Grant MP, Harper BW, Krause-Heuer AM, Manohar M, Orkey N, Aldrich-Wright JR (2011) Transition metal based anticancer drugs. Curr Top Med Chem 11:521–542. doi:10.2174/156802611794785226 CrossRefPubMedGoogle Scholar
  21. Go ML, Wu X, Liu XL (2005) Chalcones: an update on cytotoxic and chemoprotective properties. Curr Med Chem 12:483–499. doi:10.2174/0929867053363153 CrossRefGoogle Scholar
  22. Krajčiová D, Melník M, Havránek E, Forgácsová A, Mikuš P (2014) Copper compounds in nuclear medicine and oncology. J Coord Chem 67:1493–1519. doi:10.1080/00958972.2014.915966 CrossRefGoogle Scholar
  23. Lessa JA, Mendes IC, da Silva PRO, Soares MA, dos Santos RG, Speziali NL, Romeiro NC, Barreiro EJ, Beraldo H (2010) 2-Acetylpyridine thiosemicarbazones: cytotoxic activity in nanomolar doses against malignant gliomas. Eur J Med Chem 45:5671–5677. doi:10.1016/j.ejmech.2010.09.021 CrossRefPubMedGoogle Scholar
  24. Lessa JA, Guerra JC, de Miranda LF, Romeiro CFD, Da Silva JG, Mendes IC, Speziali NL, Souza-Fagundes EM, Beraldo H (2011) Gold(I) complexes with thiosemicarbazones: cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity. J Inorg Biochem 105:1729–1739. doi:10.1016/j.jinorgbio.2011.09.008 CrossRefPubMedGoogle Scholar
  25. Lessa JA, Ferraz KSO, Guerra JC, de Miranda LF, Romeiro CFD, Souza-Fagundes EM, Barbeira PJS, Beraldo H (2012a) 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 25:587–598. doi:10.1007/s10534-012-9547-5 CrossRefPubMedGoogle Scholar
  26. Lessa JA, Parrilha GL, Beraldo H (2012b) Gallium complexes as new promising metallodrug candidates. Inorg Chim Acta 393:53–63. doi:10.1016/j.ica.2012.06.003 (and references therein)CrossRefGoogle Scholar
  27. Lippert B (1999) Cisplatin. Chemistry and biochemistry of a leading anticancer drug. Wiley, WeinheimCrossRefGoogle Scholar
  28. Mendes IC, Moreira JP, Ardisson JD, dos Santos RG, da Silva PRO, Garcia I, Castiñeiras A, Beraldo H (2008) Organotin(IV) complexes of 2-pyridineformamide-derived thiosemicarbazones: antimicrobial and cytotoxic effects. Eur J Med Chem 43:1454–1461. doi:10.1016/j.ejmech.2007.09.016 CrossRefPubMedGoogle Scholar
  29. Meng LH, Liao ZY, Pommier Y (2003) Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem 3:305–320. doi:10.2174/1568026033452546 CrossRefPubMedGoogle Scholar
  30. Merlino A, Benitez D, Chavez S, da Cunha J, Hernández P, Tinoco LW, Campillo NE, Páez JA, Cerecetto H, González M (2010) Development of second generation amidinohydrazones, thio- and semicarbazones as Trypanosoma cruzi-inhibitors bearing benzofuroxan and benzimidazole 1,3-dioxide core scaffolds. Med Chem Commun 1:216–228. doi:10.1039/c0md00085 CrossRefGoogle Scholar
  31. Mosmann Y (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4 CrossRefPubMedGoogle Scholar
  32. Mura P, Camalli M, Bindoli A, Sorrentino F, Casini A, Gabbiani C, Corsini M, Zanello P, Rigobello MP, Messori L (2007) Activity of rat cytosolic thioredoxin reductase is strongly decreased by trans-[bis(2-amino-5-methylthiazole)tetrachlororuthenate(III)]: first report of relevant thioredoxin reductase inhibition for a ruthenium compound. J Med Chem 50:5871–5874. doi:10.1021/jm0708578 CrossRefPubMedGoogle Scholar
  33. Nobili S, Mini E, Landini I, Gabbiani C, Casini A, Messori L (2010) Gold compounds as anticancer agents: chemistry, cellular pharmacology, and preclinical studies. Med Res Rev 30:550–580. doi:10.1002/med.20168 PubMedGoogle Scholar
  34. Nowakowska Z (2007) A review of anti-infective and anti-inflammatory chalcones. Eur J Med Chem 42:125–137. doi:10.1016/j.ejmech.2006.09.019 CrossRefPubMedGoogle Scholar
  35. Oehninger L, Stefanopoulou M, Alborzinia H, Schur J, Ludewig S, Namikawa K, Muñoz-Castro A, Köster RW, Baumann K, Wölfl S, Sheldrick WS, Ott I (2013) Evaluation of arene ruthenium(II) N-heterocyclic carbene complexes as organometallics interacting with thiol and selenol containing biomolecules. Dalton Trans 42:1657–1666. doi:10.1039/c2dt32319b CrossRefPubMedGoogle Scholar
  36. Ott I (2009) On the medicinal chemistry of gold complexes as anticancer drugs. Coord Chem Rev 253:1670–1681. doi:10.1016/j.ccr.2009.02.019 CrossRefGoogle Scholar
  37. Ott I, Qian X, Xu Y, Vlecken DHW, Marques IJ, Kubutat D, Will J, 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 52:763–770. doi:10.1021/jm8012135 CrossRefPubMedGoogle Scholar
  38. Parrilha GL, Ferraz KSO, Lessa JA, de Oliveira KN, Rodrigues BL, Ramos JP, Souza-Fagundes EM, Ott I, Beraldo H (2014) Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone: cytotoxicity and effect on the enzymatic activity of thioredoxin reductase and glutathione reductase. Eur J Med Chem 84:537–544. doi:10.1016/j.ejmech.2014.07.055 CrossRefPubMedGoogle Scholar
  39. Powis G, Wipf P, Lynch SM, Birmingham A, Kirkpatrick DL (2006) Molecular pharmacology and antitumor activity of palmarumycin-based inhibitors of thioredoxin reductase. Mol Cancer Ther 5:630–636. doi:10.1158/1535-7163.MCT-05-0487 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Teitz Y, Ronen D, Vansover A, Stematsky T, Riggs JL (1994) Inhibition of human immunodeficiency virus by N-methylisatin-β4′:β4′-diethylthiosemicarbazone and N-allylisatin-β4′:4′-diallythiosemicarbazone. Antiviral Res 24:305–314. doi:10.1016/0166-3542(94)90077-9 CrossRefPubMedGoogle Scholar
  41. Thapa P, Jun KY, Kadayat TM, Park C, Zheng Z, Magar TBT, Bist G, Shrestha A, Na Y, Kwon Y, Lee ES (2015) Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents. Bioorg Med Chem 23:6454–6466. doi:10.1016/j.bmc.2015.08.018 CrossRefPubMedGoogle Scholar
  42. Tiekink ERT (2002) Antimony and bismuth compounds in oncology. Crit Rev Oncol Hemat 42:217–224. doi:10.1016/S1040-8428(01)00217-7 CrossRefGoogle Scholar
  43. Ulukaya E, Colakogullari M, Wood EJ (2004) Interference by anti-cancer chemotherapeutic agents in the MTT-tumor chemosensitivity assay. Chemotherapy 50:43–50. doi:10.1159/000077285 CrossRefPubMedGoogle Scholar
  44. Vieira S, Castelli S, Desideri A (2015) Importance of a stable topoisomerase IB clamping for an efficient DNA processing: effect of the Lys369Glu mutation. Int J Biol Macromol 81:76–82. doi:10.1016/j.ijbiomac.2015.07.044 CrossRefPubMedGoogle Scholar
  45. Zeglis BM, Divilov V, Lewis JS (2011) Role of metalation in the topoisomerase IIα inhibition and antiproliferation activity of a series of α-heterocyclic-N4-substituted thiosemicarbazones and their Cu(II) complexes. J Med Chem 54:2391–2398. doi:10.1021/jm101532u CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Luciana B. P. Sâmia
    • 1
  • Gabrieli L. Parrilha
    • 1
  • Jeferson G. Da Silva
    • 2
  • Jonas P. Ramos
    • 3
  • Elaine M. Souza-Fagundes
    • 3
  • Silvia Castelli
    • 4
  • Venn Vutey
    • 4
  • Alessandro Desideri
    • 4
  • Heloisa Beraldo
    • 1
  1. 1.Departamento de QuímicaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Departamento de FarmáciaUniversidade Federal de Juiz de Fora (UFJF)Governador ValadaresBrazil
  3. 3.Departamento de Fisiologia e BiofísicaUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  4. 4.Department of BiologyUniversity of Rome “Tor Vergata”RomeItaly

Personalised recommendations