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Investigational New Drugs

, Volume 28, Issue 4, pp 421–432 | Cite as

Cytotoxic activities of new iron(III) and nickel(II) chelates of some S-methyl-thiosemicarbazones on K562 and ECV304 cells

  • Belkıs Atasever
  • Bahri Ülküseven
  • Tülay Bal-Demirci
  • Serap Erdem-Kuruca
  • Zeynep Solakoğlu
PRECLINICAL STUDIES

Summary

The S-methyl-thiosemicarbazones of the 2-hydroxy-R-benzaldehyde (R= H, 3-OH 3-OCH3 or 4-OCH3) reacted with the corresponding aldehydes in the presence of FeCl3 and NiCl2. New ONNO chelates of iron(III) and nickel(II) with hydroxy- or methoxy-substitued N 1,N 4-diarylidene-S-methyl-thiosemicarbazones were characterized by means of elemental analysis, conductivity and magnetic measurements, UV-Vis, IR and 1H-NMR spectroscopies. Cytotoxic activities of the compounds were determined using K562 chronic myeloid leukemia and ECV304 human endothelial cell lines by MTT assay. It was determined that monochloro N 1-4-methoxysalicylidene-N 4-4-methoxysalicylidene-S-methyl-thiosemicarbazidato-iron(III) complex showed selective anti-leukemic effects in K562 cells while has no effect in ECV304 cells in the 0.53 μg/ml (IC50) concentrations. Also, some methoxy-substitued nickel(II) chelates exhibit high cytotoxic activitiy against both of these cell lines in low concentrations. Cytotoxicity data were evaluated depending on cell lines origin and position of the substituents on aromatic rings.

Keywords

Thiosemicarbazone Iron complex Nickel complex Cytotoxicity MTT 

Notes

Acknowledgement

This work was supported by the Research Fund of Istanbul University. Project number, 516/05052006.

References

  1. 1.
    Simmons G, Hobson LB, Resnick A, De Nicola R, Bennett RH, Rake G (1950) Human pharmacology of p-formylacetanilide thiosemicarbazone. Trans Annu Meet Natl Tuberc Assoc 46:124–127PubMedGoogle Scholar
  2. 2.
    Gialdi F, Ponci R (1951) Antibacterial activity of quinoline derivatives. Preparation and in vitro antibacterial activity of 6-6-diquinolylsulfone and various thiosemicarbazones of quinoline aldehydes. Farmaco 6(3):332–336PubMedGoogle Scholar
  3. 3.
    West DX, Liberta AE, Padhye SB, Chikate RC, Sonawane PBV, Kumbhar AS, Yerande RG (1993) Thiosemicarbazone complexes of copper(II): structural and biological studies. Coord Chem Rev 123:49–71. doi: 10.1016/0010-8545(93)85052-6 CrossRefGoogle Scholar
  4. 4.
    Maccari R, Ottanã R, Monforte F, Vigorita MG (2002) In vitro antimycobacterial activities of 2′-monosubstituted ısonicotinohydrazides and their cyanoborane adducts. Antimicrob Agents Chemother 46(2):294–299. doi: 10.1128/AAC.46.2.294-299.2002 CrossRefPubMedGoogle Scholar
  5. 5.
    Beraldo H, Gambino D (2004) The wide pharmacological versatility of semicarbazones, thiosemicarbazones and their metal complexes. Mini Rev Med Chem 4(1):31–40. doi: 10.2174/1389557043487484 CrossRefPubMedGoogle Scholar
  6. 6.
    Ainscough EW, Brodie AM, Denny WA, Finlay GJ, Ranford JD (1998) Nitrogen, sulfur and oxygen donor adducts with copper(II) complexes of antitumor 2-formylpyridinethiosemicarbazone analogs: physicochemical and cytotoxic studies. J Inorg Biochem 70(3–4):175–185. doi: 10.1016/S0162-0134(98)10011-9 CrossRefPubMedGoogle Scholar
  7. 7.
    Hall IH, Lackey CB, Kistler TD Jr, Durham RW, Jouad EM, Khan M, Thanh XD, Djebbar-Sid S, Benali-Baitich O, Bouet GM (2000) Cytotoxicity of copper and cobalt complexes of furfural semicarbazone and thiosemicarbazone derivatives in murine and human tumor cell lines. Pharmazie 55(12):937–941PubMedGoogle Scholar
  8. 8.
    Sau DK, Butcher RJ, Chaudhuri S, Saha N (2003) Spectroscopic, structural and antibacterial properties of copper(II) complexes with bio-relevant 5-methyl-3-formylpyrazole N(4)-benzyl-N(4)-methylthiosemicarbazone. Mol Cell Biochem 253(1–2):21–29. doi: 10.1023/A:1026041032078 CrossRefPubMedGoogle Scholar
  9. 9.
    Padhye S, Afrasiabi Z, Sinn E, Fok J, Mehta K, Rath N (2005) Antitumor metallothiosemicarbazonates: structure and antitumor activity of palladium complex of phenanthrenequinone thiosemicarbazone. Inorg Chem 44(5):1154–1156. doi: 10.1021/ic048214v CrossRefPubMedGoogle Scholar
  10. 10.
    Rebolledo AP, Vieites M, Gambino D, Piro OE, Castellano EE, Zani CL, Souza-Fagundes EM, Teixeira LR, Batista AA, Beraldo H (2005) Palladium(II) complexes of 2-benzoylpyridine-derived thiosemicarbazones: spectral characterization, structural studies and cytotoxic activity. J Inorg Biochem 99(3):698–706. doi: 10.1016/j.jinorgbio.2004.11.022 CrossRefPubMedGoogle Scholar
  11. 11.
    Mishra V, Pandeya SN, Pannecouque C, Witvrouw M, De Clercq E (2002) Anti-HIV activity of thiosemicarbazone and semicarbazone derivatives of (±)-3-menthone. Arch Pharm 335(5):183–186. doi: 10.1002/1521-4184(200205)335:5<183::AID-ARDP183>3.0.CO;2-U CrossRefGoogle Scholar
  12. 12.
    Varadinova T, Kovala-Demertzi D, Rupelieva M, Demertzis M, Genova P (2001) Antiviral activity of platinum (II) and palladium (II) complexes of pyridine-2-carbaldehyde thiosemicarbazone. Acta Virol 45(2):87–94PubMedGoogle Scholar
  13. 13.
    Genova P, Varadinova T, Matesanz AI, Marinova D, Souza P (2004) Toxic effects of bis(thiosemicarbazone) compounds and its palladium(II) complexes on herpes simplex virus growth. Toxicol Appl Pharmacol 197(2):107–112. doi: 10.1016/j.taap. 2004.02.006 CrossRefPubMedGoogle Scholar
  14. 14.
    Bal TR, Anand B, Yogeeswari P, Sriram D (2005) Synthesis and evaluation of anti-HIV activity of isatin β-thiosemicarbazone derivatives. Bioorg Med Chem Lett 15(20):4451–4455. doi: 10.1016/j.bmcl.2005.07.046 CrossRefPubMedGoogle Scholar
  15. 15.
    Amlacher R (1985) Route-dependent different relations between acute and subacute toxicity of the potential antiviral agent benzoxazolyl-2-formyl-S-ethyl-isothiosemicarbazone in mice. Pharmazie 40(2):132–133PubMedGoogle Scholar
  16. 16.
    Cocco MT, Congiu C, Onnis V, Pellerano ML, De Logu A (2002) Synthesis and antimycobacterial activity of new S-alkylisothiosemicarbazone derivatives. Bioorg Med Chem 10(3):501–506. doi: 10.1016/S0968-0896(01)00310-8 CrossRefPubMedGoogle Scholar
  17. 17.
    De Logu A, Saddi M, Onnis V, Sanna C, Congıu C, Borgna R, Cocco MT (2005) In vitro antimycobacterial activity of newly synthesised S-alkylisothiosemicarbazone derivatives and synergistic interactions in combination with rifamycins against Mycobacterium avium. Int J Antimicrob Agents 26(1):28–32. doi: 10.1016/j.ijantimicag.2005.03.005 CrossRefPubMedGoogle Scholar
  18. 18.
    Kızılcıklı İ, Kurt Y, Akkurt B, Genel AY, Birteksöz S, Ötük G, Ülküseven B (2007) Antimicrobial activity of a series of thiosemicarbazones and their ZnII and PdII complexes. Folia Microbiol (Praha) 21(1):15–25. doi: 10.1007/BF02932132 Google Scholar
  19. 19.
    Bal Demirci T, Atasever B, Solakoğlu Z, Erdem-Kuruca S, Ülküseven B (2007) Synthesis, characterisation and cytotoxic properties of the N1, N4- diarylidene-S-methyl-thiosemicarbazone chelates with Fe(III) and Ni(II). Eur J Med Chem 42(2):161–167. doi: 10.1016/j.ejmech.2006.09.004 CrossRefGoogle Scholar
  20. 20.
    Matesanz AI, Souza P (2007) Palladium and platinum 3, 5-diacetyl-1, 2, 4-triazol bis(thiosemicarbazones): chemistry, cytotoxic activity and structure-activity relationships. J Inorg Biochem 101:245–253. doi: 10.1016/j.jinorgbio.2006.09.024 CrossRefPubMedGoogle Scholar
  21. 21.
    Kalinowski DS, Yu Y, Sharpe PC, Islam M, Liao YT, Lovejoy DB, Kumar N, Bernhardt PV, Richardson DR (2007) Design, synthesis, and characterization of novel ıron chelators: structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents. J Med Chem 50:3716–3729. doi: 10.1021/jm070445z CrossRefPubMedGoogle Scholar
  22. 22.
    Quiroga AG, Pérez JM, Lopez-Solera I, Masaguer JR, Luque A, Roman P, Edwards A, Alonso C, Navarro-Ranninger C (1998) Novel tetranuclear orthometalated complexes of Pd(II) and Pt(II) Derived from p-isopropylbenzaldehyde thiosemicarbazone with cytotoxic activity in cis-DDP resistant tumor cell lines. Interaction of these complexes with DNA. J Med Chem 41:1399–1408. doi: 10.1021/jm970520d CrossRefPubMedGoogle Scholar
  23. 23.
    Odenike OM, Larson RA, Gajria D, Dolan ME, Delaney SM, Karrison TG, Ratain MJ, Stock W (2008) Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia. Invest New Drugs 26(3):233–239. doi: 10.1007/s10637-008-9115-6 CrossRefPubMedGoogle Scholar
  24. 24.
    Gojo I, Tidwell ML, Greer J, Takebe N, Seiter K, Pochron MF, Johnson B, Sznol M, Karp JE (2007) Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies. Leuk Res 31(9):1165–1173. doi: 10.1016/j.leukres.2007.01.004 CrossRefPubMedGoogle Scholar
  25. 25.
    Ma B, Goh BC, Tan EH, Lam KC, Soo R, Leong SS, Wang LZ, Mo F, Chan AT, Zee B, Mok T (2008) A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest New Drugs 26(2):169–173. doi: 10.1007/s10637-007-9085-0 CrossRefPubMedGoogle Scholar
  26. 26.
    Traynor AM, Lee JW, Bayer GK, Tate JM, Thomas SP, Mazurczak M, Graham DL, Kolesar JM, Schiller JH (2009) A phase II trial of Triapine(R) (NSC# 663249) and gemcitabine as second line treatment of advanced non-small cell lung cancer: Eastern Cooperative Oncology Group Study 1503. Invest New Drugs . doi: 10.1007/s10637-009-9230-z Google Scholar
  27. 27.
    Shao J, Zhou B, Chu B, Yen Y (2006) Ribonucleotide reductase ınhibitors and future drug design. Curr Cancer Drug Targets 6:409–431. doi: 10.2174/156800906777723949 CrossRefPubMedGoogle Scholar
  28. 28.
    Yee KW, Cortes J, Ferrajoli A, Garcia-Manero G, Verstovsek S, Wierda W, Thomas D, Faderl S, King I, O’brien SM, Jeha S, Andreeff M, Cahill A, Sznol M, Giles FJ (2006) Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leuk Res 30(7):813–822. doi: 10.1016/j.leukres.2005.12.013 CrossRefPubMedGoogle Scholar
  29. 29.
    Garcia-Manero G, Faderl S, O’Brien S, Cortes J, Talpaz M, Kantarjian HM (2003) Chronic myelogenous leukemia: a review and update of therapeutic strategies. Cancer 98(3):437–457. doi: 10.1002/cncr.11520 CrossRefPubMedGoogle Scholar
  30. 30.
    Horner M-JD, Ries LAG (2005) Leukemia in SEER Cancer Statistics Review, 1975–2003, National Cancer Institute. http://seer.cancer.gov/csr/1975-2003/, SEER Survival Monograph, 29:243–250
  31. 31.
    Yuan J, Lovejoy DB, Richardson DR (2004) Novel di-2-pyridyl-derived iron chelators with marked and selective antitumor activity: in vitro and in vivo assessment. Blood 104(5):1450–1458. doi: 10.1182/blood-2004-03-0868 CrossRefPubMedGoogle Scholar
  32. 32.
    Mossman N-T (1983) Rapid colorimetric assay for cellular growth and survivals: Application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi: 10.1016/0022-1759(83)90303-4 CrossRefGoogle Scholar
  33. 33.
    Bal T, Ülküseven B (2004) Hydroxy and methoxy substituted N1, N4-diarylidene-S-methylthiosemicarbazone iron(III) and nickel(II) complexes. Transit Met Chem 29:880–884. doi: 10.1007/s11243-004-2240-y CrossRefGoogle Scholar
  34. 34.
    Leovac VM, Jovanovic LS, Bjelica LJ, Cesljevic VI (1989) Transition metal complexes with the thiosemicarbazide-based ligands—III. Synthesis, physico-chemical properties and voltammetric characterization of some Fe III complexes with ter- and quadridentate S-methylisothiosemicarbazide derivatives. Polyhedron 8:135–141. doi: 10.1016/S0277-5387(00)86494-3 CrossRefGoogle Scholar
  35. 35.
    Fostiak LM, Garcia I, Swearingen JK, Bermejo E, Castineiras A, West DX (2003) Structural and spectral characterization of transition metal complexes of 2-pyridine formamide N(4)-dimethylthiosemicarbazone. Polyhedron 22:83–92. doi: 10.1016/S0277-5387(02)01330-X CrossRefGoogle Scholar
  36. 36.
    Beraldo H, Boyd LP, West DX (1998) Copper(II) and nickel(II) complexes of glyoxaldehyde bis-[N(3)-substituted thiosemicarbazones. Transit Met Chem 23:67–71. doi: 10.1023/A:1006958018049 CrossRefGoogle Scholar
  37. 37.
    Kobayashi H, Yanagawa Y, Osada H, Minami S, Shimuzu M (1973) Electronic spectra of high-spin ıron(III) tetraphenylporphins. Bull Chem Soc Jpn 46:1471–1479. doi: 10.1246/bcsj.46.1471 CrossRefGoogle Scholar
  38. 38.
    Cheng RJ, Latos-Grazynski L, Balch AL (1982) Preparation and characterization of some hydroxy complexes of iron(III) porphyrins. Inorg Chem 21:2412–2418. doi: 10.1021/ic00136a057 CrossRefGoogle Scholar
  39. 39.
    Fabretti AC, Forghieri F, Giusti A, Preti C, Tosi G (1984) The syntheses and properties of cobalt(II), nickel(II) and copper(II) complexes with some heterocyclic dithiocarbamates. Inorg Chim Acta 86:127–131. doi: 10.1016/S0020-1693(00)82333-6 CrossRefGoogle Scholar
  40. 40.
    Criado JJ, Carrasco A, Marcias B, Salas JM, Madarde M, Castillo M (1989) New PtS4 chromophores of dithiocarbamates derived from α-amino acids: synthesis, characterization and thermal behaviour. Inorg Chim Acta 160:37–42. doi: 10.1016/S0020-1693(00)85396-7 CrossRefGoogle Scholar
  41. 41.
    Arion VB, Kravtsov VC, Goddard R, Bill E, Gradinaru JI, Gerbeleu NV, Levitschi V, Vezin H, Simonov YA, Lipkowski J, Bel’skii VK (2001) Oxovanadium(IV) and oxovanadium(IV)-barium(II) complexes with heterotopic macrocyclic ligands based on isothiosemicarbazide. Inorg Chim Acta 317:33–44. doi: 10.1016/S0164-1212(00)00107-2 CrossRefGoogle Scholar
  42. 42.
    Chang CSJ, Enemark JH (1991) Spectroscopic and electrochemical studies of monomeric oxomolybdenum(V) complexes with five-membered chelate rings and alkoxo or alkanethiolato ligands. Inorg Chem 30:683–688. doi: 10.1021/ic00004a017 CrossRefGoogle Scholar
  43. 43.
    Ferrari MB, Fava GG, Leporati E, Pelosi G, Rossi R, Tarasconi P, Albertini R, Bonati A, Lunghi P, Pinelli S (1998) Synthesis, characterisation and biological activity of three copper (II) complexes with a modified nitrogenous base: 5-formyluracil thiosemicarbazone. J Inorg Biochem 70(2):145–154. doi: 10.1016/S0162-0134(98)10012-0 CrossRefPubMedGoogle Scholar
  44. 44.
    Ferrari MB, Bisceglie F, Pelosi G, Tarasconi P, Albertin R, Bonati A, Lunghi P, Pinelli S (2001) Synthesis, characterisation, X-ray structure and biological activity of three new 5-formyluracil thiosemicarbazone complexes. J Inorg Biochem 83(2–3):169–179. doi: 10.1016/S0162-0134(00)00181-1 CrossRefPubMedGoogle Scholar
  45. 45.
    Buschini A, Pinelli S, Pellacani C, Giordani F, Belicchi Ferrari M, Bisceglie F, Giannetto M, Pelosi G, Tarasconi P (2009) Synthesis, characterization and deepening in the comprehension of the biological action mechanisms of a new nickel complex with antiproliferative activity. J Inorg Biochem 103(5):666–677. doi: 10.1016/j.jinorgbio.2008.12.016 CrossRefPubMedGoogle Scholar
  46. 46.
    Li J, Li-mou Z, King I, Doyle TW, Chen S-H (2001) Syntheses and Antitumor Activities of Potent Inhibitors of Ribonucleotide Reductase: 3-Amino-4-Methylpyridine-2-Carboxaldehyde-Thiosemicarbazone (3-Amp), 3-Amino-Pyridine-2-Carboxaldehyde-Thiosemicarbazone (3-Ap) and its Water-Soluble Prodr. Curr Med Chem 8:121–133PubMedGoogle Scholar
  47. 47.
    Kovala-Demertzi D, Papageorgiou A, Papathanasis L, Alexandratos A, Dalezis P, Miller JR, Mavroudis A (2009) In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine andcontaining ring incorporated at N(4)-position: Synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents. Eur J Med Chem 44:1296–1302. doi: 10.1016/j.ejmech.2008.08.007 CrossRefPubMedGoogle Scholar
  48. 48.
    Afrasiabi Z, Sinn E, Chen J, Ma Y, Rheingold AL, Zakharov LN, Rath N, Padhye S (2004) Appended 1, 2-naphthoquinones as anticancer agents 1:synthesis, structural, spectral and antitumor activities of ortho-naphthaquinone thiosemicarbazone and its transition metal complexes. Inorg Chim Acta 357:271–278. doi: 10.1016/S0020-1693(03)00484-5 CrossRefGoogle Scholar
  49. 49.
    Chen J, Yue-wern H, Liu G, Afrasiabi Z, Sinn E, Padhye S, Ma Y (2004) The cytotoxicity and mechanisms of 1, 2-naphthoquinone thiosemicarbazone and its metal derivatives against MCF-7 human breast cancer cells. Toxicol Appl Pharmacol 197:40–48. doi: 10.1016/j.taap.2004.02.004 CrossRefPubMedGoogle Scholar
  50. 50.
    Richardson DR, Sharpe PC, Lovejoy DB, Senaratne D, Kalinowski DS, Islam M, Bernhardt PV (2006) Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form ıron complexes with redox activity. J Med Chem 49:6510–6521. doi: 10.1021/jm0606342 CrossRefPubMedGoogle Scholar
  51. 51.
    Ülküseven B, Bal T, Sahin M (2006) Novel Pd(II) templates of N(1), N(4)-diarylidene-S-methyl-, ethyl- and allylthiosemicarbazones. Rev Inorg Chem 26(4):367–378Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Belkıs Atasever
    • 1
  • Bahri Ülküseven
    • 2
  • Tülay Bal-Demirci
    • 2
  • Serap Erdem-Kuruca
    • 3
  • Zeynep Solakoğlu
    • 3
  1. 1.Faculty of Engineering and Natural SciencesSabanci UniversityTuzlaTürkiye
  2. 2.Department of ChemistryIstanbul UniversityAvcilarTürkiye
  3. 3.Physiology Department, Istanbul Medical FacultyIstanbul UniversityIstanbulTürkiye

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