Biological Trace Element Research

, Volume 154, Issue 1, pp 111–119 | Cite as

Development of New Zinc Dithiosemicarbazone Complex for Use as Oral Antidiabetic Agent

  • Saori Kadowaki
  • Masayuki Munekane
  • Yoji Kitamura
  • Makoto Hiromura
  • Shinichiro Kamino
  • Yutaka Yoshikawa
  • Hideo Saji
  • Shuichi Enomoto


The increasing prevalence of diabetes mellitus (DM) worldwide has underscored the urgency of developing an efficient therapeutic agent. Recently, Zn complexes have been attracting attention due to their antidiabetic activity. In this study, we designed and synthesized a new Zn complex, Zn-3,4-heptanedione-bis(N 4-methylthiosemicarbazonato) (Zn-HTSM), characterized its physicochemical properties, and examined its antidiabetic activity in KK-Ay type 2 DM model mice. It was demonstrated that Zn-HTSM has adequate lipophilicity for the cellular permeability, shows potent hypoglycemic activity, and improves glucose intolerance in KK-Ay mice. We also analyzed the levels of serum adipokines after continuous oral administration of Zn-HTSM. The level of serum leptin of KK-Ay mice is significantly reduced by the treatment of Zn-HTSM. Nevertheless, the levels of serum insulin and adiponectin were not improved. These data suggested that the Zn-HTSM acts on the leptin metabolism. Our present studies indicate that Zn-HTSM is a candidate oral antidiabetic agent for the treatment of type 2 DM.


Zinc dithiosemicarbazone complexes Oral antidiabetic agents Hypoglycemic activity Glucose intolerance Leptin resistance 


  1. 1.
    Kahn SE, Hull RL, Utzschneider KM (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444:840–846PubMedCrossRefGoogle Scholar
  2. 2.
    Shaw JE, Sicree RA, Zimmet PZ (2010) Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 87:4–14PubMedCrossRefGoogle Scholar
  3. 3.
    Guilherme A, Virbasius JV, Puri V, Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9:367–377PubMedCrossRefGoogle Scholar
  4. 4.
    Bays H, Mandarino L, DeFronzo RA (2004) Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 89:463–478PubMedCrossRefGoogle Scholar
  5. 5.
    Falcão-Pires I, Castro-Chaves P, Miranda-Silva D, Lourenço AP, Leite-Moreira AF (2012) Physiological, pathological and potential therapeutic roles of adipokines. Drug Discovery Today 17:880–889PubMedCrossRefGoogle Scholar
  6. 6.
    Rosen ED, Spiegelman BM (2006) Adipocytes as regulator of energy balance and glucose homeostasis. Nature 444:847–853PubMedCrossRefGoogle Scholar
  7. 7.
    Myers MG, Cowley MA, Munzberg H (2008) Mechanisms of leptin action and leptin resistance. Annu Rev Physiol 70:537–556PubMedCrossRefGoogle Scholar
  8. 8.
    Maret W, Sandstead HH (2006) Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol 20:3–18PubMedCrossRefGoogle Scholar
  9. 9.
    Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr 17:109–115PubMedCrossRefGoogle Scholar
  10. 10.
    Salgueiro MJ, Krebs N, Zubillaga MB, Weill R, Postaire E, Lysionek AE, Caro RA, De Paoli T, Hager A, Boccio J (2001) Zinc and diabetes mellitus—is there a need of zinc supplementation in diabetes mellitus patients? Biol Trace Elem Res 81:215–228PubMedCrossRefGoogle Scholar
  11. 11.
    Chen MD, Liou SJ, Lin PY, Yang VC, Alexander PS, Lin WH (1998) Effects of zinc supplementation on the plasma glucose level and insulin activity in genetically obese (ob/ob) mice. Biol Trace Elem Res 61:303–311PubMedCrossRefGoogle Scholar
  12. 12.
    Anderson RA, Roussel AM, Zouari N, Mahjoub S, Matheau JM, Kerkeni A (2001) Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. J Am Coll Nutr 20:212–218PubMedGoogle Scholar
  13. 13.
    Kinlaw WB, Levine AS, Morley JE, Silvis SE, McClain CJ (1983) Abnormal zinc metabolism in type II diabetes mellitus. Am J Med 75:273–277PubMedCrossRefGoogle Scholar
  14. 14.
    Sakurai H, Katoh A, Kiss T, Jakusch T, Hattori M (2010) Metallo-allixinate complexes with anti-diabetic and anti-metabolic syndrome activities. Metallomics 2:670–682PubMedCrossRefGoogle Scholar
  15. 15.
    Adachi Y, Yoshida J, Kodera Y, Kato A, Yoshikawa Y, Kojima Y, Sakurai H (2004) A new insulin-mimetic bis(allixinato)zinc(II) complex: structure–activity relationship of zinc(II) complexes. J Biol Inorg Chem 9:885–893PubMedCrossRefGoogle Scholar
  16. 16.
    Yoshikawa Y, Murayama A, Adachi Y, Sakurai H, Yasui H (2011) Challenge of studies on the development of new Zn complexes (Zn(opt)(2)) to treat diabetes mellitus. Metallomics 3:686–692PubMedCrossRefGoogle Scholar
  17. 17.
    Yoshikawa Y, Adachi Y, Sakurai H (2007) A new type of orally active anti-diabetic Zn(II)-dithiocarbamate complex. Life Sci 80:759–766PubMedCrossRefGoogle Scholar
  18. 18.
    Karmaker S, Saha TK, Yoshikawa Y, Sakurai H (2009) A zinc(II)/poly(g-glutamic acid) complex as an oral therapeutic for the treatment of type-2 diabetic KKAy mice. Macromol Biosci 9:279–286PubMedCrossRefGoogle Scholar
  19. 19.
    Basuki W, Hiromura M, Sakurai H (2007) Insulinomimetic Zn complex (Zn(opt)2) enhances insulin signaling pathway in 3T3-L1 adipocytes. J Inorg Biochem 101:692–699PubMedCrossRefGoogle Scholar
  20. 20.
    Nakayama A, Hiromura M, Adachi Y, Sakurai H (2008) Molecular mechanism of antidiabetic zinc–allixin complexes: regulations of glucose utilization and lipid metabolism. J Biol Inorg Chem 13:675–684PubMedCrossRefGoogle Scholar
  21. 21.
    Naito Y, Yoshikawa Y, Yasui H (2011) Cellular mechanism of zinc-hinokitiol complexes in diabetes mellitus. Bull Chem Soc Jpn 84:298–305CrossRefGoogle Scholar
  22. 22.
    Ishiki M, Klip A (2005) Minireview: recent developments in the regulation of glucose transporter-4 traffic: new signals, locations, and partners. Endocrinology 146:5071–5078PubMedCrossRefGoogle Scholar
  23. 23.
    Kasuga NC, Sekino K, Ishikawa M, Honda A, Yokoyama M, Nakano S, Shimada N, Koumo C, Nomiya K (2003) Synthesis, structural characterization and antimicrobial activities of 12 zinc(II) complexes with four thiosemicarbazone and two semicarbazone ligands. J Inorg Biochem 96:298–310PubMedCrossRefGoogle Scholar
  24. 24.
    David PH (1972) Physico-chemical properties of the antitumor agent, 3-ethoxy-2-oxobutyraldehyde bis (thiosemicarbazonato) copper(II). Bioinorg Chem 1:255–271CrossRefGoogle Scholar
  25. 25.
    Kubota M, Iida Y, Magata Y, Kitamura Y, Kawashima H, Saji H (2000) Mechanisms of [2,3-butanedione bis(N-4-dimethylthiosemicarbazone)]zinc (Zn-ATSM(2))-induced protection of cultured hippocampal neurons against N-methyl-d-aspartate receptor-mediated glutamate cytotoxicity. Jpn J Pharmacol 84:334–338PubMedCrossRefGoogle Scholar
  26. 26.
    Green MA, Klippenstein DL, Tennison JR (1988) Copper(II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET. J Nucl Med 29:1549–1557PubMedGoogle Scholar
  27. 27.
    Christlieb M, Holland JP, Dilworth JR (2010) Investigation of the UV–vis absorption of bis(N-methylthiosemicarbazonato) zinc Zn[ATSM]. Inorg Chim Acta 363:1133–1139CrossRefGoogle Scholar
  28. 28.
    Cowley AR, Davis J, Dilworth JR, Donnelly PS, Dobson R, Nightingale A, Peach J.M, Shore B, Kerr D, Seymour L (2005) Fluorescence studies of the intra-cellular distribution of zinc bis(thiosemicarbazone) complexes in human cancer cells. Chem Commun 845–847Google Scholar
  29. 29.
    Donnelly PS, Caragounis A, Du T, Laughton KM, Volitakis I, Cherny RA, Sharples RA, Hill AF, Li QX, Masters CL, Barnham KJ, White AR (2008) Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide. J Biol Chem 283:4568–4577PubMedCrossRefGoogle Scholar
  30. 30.
    Betts HM, Barnard PJ, Bayly SR, Dilworth JR, Gee AD, Holland JP (2008) Controlled axial coordination: solid-phase synthesis and purification of metallo-radiopharmaceuticals. Angew Chem-Int Edit 47:8416–8419CrossRefGoogle Scholar
  31. 31.
    Hayase M, Ogawa Y, Katsuura G, Shintaku H, Hosoda K, Nakao K (1996) Regulation of obese gene expression in KK mice and congenic lethal yellow obese KKAy mice. Am J Physiol Endocrinol Metab 271:E333–E339Google Scholar
  32. 32.
    Yoshikawa Y, Kawabe K, Tadokoro M, Suzuki Y, Yanagihara N, Nakayama A, Sakurai H, Kojima Y (2002) New zinc(II) complexes with tetradentate amino acid derivatives: structure characterization, solution chemistry, and in vitro insulinomimetic activity. Bull Chem Soc Jpn 75:2423–2432CrossRefGoogle Scholar
  33. 33.
    Haase H, Maret W (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291:289–298PubMedCrossRefGoogle Scholar
  34. 34.
    Varela L, Horvath TL (2012) Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis. EMBO Rep 13:1079–1086PubMedCrossRefGoogle Scholar
  35. 35.
    Bevan P (2001) Insulin signalling. J Cell Sci 114:1429–1430PubMedGoogle Scholar
  36. 36.
    Kellerer M, Koch M, Metzinger E, Mushack J, Capp E, Haring HU (1997) Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 40:1358–1362PubMedCrossRefGoogle Scholar
  37. 37.
    Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL (1999) Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76PubMedCrossRefGoogle Scholar
  38. 38.
    Kieffer TJ, Habener JF (2000) The adipoinsular axis: effects of leptin on pancreatic β-cells. Am J Physiol Endocrinol Metab 278:E1–E14PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Saori Kadowaki
    • 1
  • Masayuki Munekane
    • 1
  • Yoji Kitamura
    • 2
  • Makoto Hiromura
    • 3
  • Shinichiro Kamino
    • 3
  • Yutaka Yoshikawa
    • 4
  • Hideo Saji
    • 5
  • Shuichi Enomoto
    • 1
    • 3
  1. 1.Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayama UniversityKita-kuJapan
  2. 2.Advanced Science Research CenterKanazawa UniversityKanazawaJapan
  3. 3.Multiple Molecular Imaging Research LaboratoryRIKEN Center for Molecular Imaging ScienceKobeJapan
  4. 4.Department of Analytical and Bioinorganic ChemistryKyoto Pharmaceutical UniversityKyotoJapan
  5. 5.Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan

Personalised recommendations