Investigational New Drugs

, Volume 29, Issue 5, pp 932–944 | Cite as

Cytotoxicity, apoptosis and study of the DNA-binding properties of bi- and tetranuclear gallium(III) complexes with heterocyclic thiolato ligands

  • Beatriz Gallego
  • Milena R. Kaluđerović
  • Harish Kommera
  • Reinhard Paschke
  • Evamarie Hey-Hawkins
  • Torsten W. Remmerbach
  • Goran N. Kaluđerović
  • Santiago Gómez-Ruiz


The reaction of the heterocyclic thiol derivatives, 2-mercapto-1-methylimidazole (SH-imi), 5-mercapto-1-methyltetrazole (SH-tet), 2-mercaptobenzothiazole (SH-ben) and 5-phenyl-1,3,4-oxadiazole-2-thiol (SH-oxa), with trimethylgallium (1:1) afforded the dimeric or tetrameric complexes [Me2Ga(S-imi)]2 (1), [Me2Ga(S-tet)]2 (2), [Me2Ga(S-ben)]2 (3) and [Me2Ga(S-oxa)]4 (4), respectively. Molecular structures of 2 and 4 were determined by X-ray diffraction studies. The cytotoxicity of the gallium(III) complexes 14 was tested against human cell lines 8505C anaplastic thyroid cancer, A253 head and neck tumor, A549 lung carcinoma, A2780 ovarian cancer, DLD-1 colon carcinoma and compared with those of cisplatin and Ga(NO3)3. Compound 4 seems to be slightly more active against 8505C, A253 and A2780 and substantially more active than all the other complexes against DLD-1, with an IC50 value of 5.49 ± 0.16 µM, very close to that of cisplatin (5.14 ± 0.12 µM). Complexes 14 were less toxic on normal human fibroblasts (WWO70327) than on the investigated tumor cell lines and more selective to cancer cells than cisplatin. DNA laddering method showed that treatment of the DLD-1 cell line with IC90 doses of 14 resulted in the induction of apoptosis. Compound 1 caused apoptosis by upregulation of caspases 2, 3 and 8. Since no activity of caspase 9 is observed, complex 1 is causing apoptosis triggered by an extrinsic pathway. DNA-interaction tests have been also carried out. Solutions of all the studied complexes have been treated with different concentrations of fish sperm DNA (FS-DNA). Modifications of the UV spectra which gave intrinsic binding constants of 3.03 × 105, 4.44 × 105, 3.02 × 106 and 5.56 × 105 M−1 for 14 were observed, however, no notable interaction with pBR322 plasmid DNA was detected.


Anticancer drugs Apoptosis Cytotoxicity Gallium Thiolato ligands 



We gratefully acknowledge financial support from the Universidad Rey Juan Carlos (postdoctoral fellowship for S.G.-R.) and Junta de Comunidades de Castilla-La Mancha (postdoctoral fellowship for B.G.). We thank the Ministry of Science and Technological Developments of the Republic of Serbia (Grant No. 142010) and Ministerium für Wirtschaft und Arbeit des Landes Sachsen-Anhalt, Deutschland (Grant No. 6003368706). We would also like to thank S. Prashar and D. Pérez-Quintanilla (Universidad Rey Juan Carlos) for useful discussions and BioSolutions Halle GmbH, Germany, for the cell culture facilities.


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Beatriz Gallego
    • 1
  • Milena R. Kaluđerović
    • 2
  • Harish Kommera
    • 3
  • Reinhard Paschke
    • 3
  • Evamarie Hey-Hawkins
    • 1
  • Torsten W. Remmerbach
    • 2
  • Goran N. Kaluđerović
    • 3
    • 4
  • Santiago Gómez-Ruiz
    • 1
    • 5
  1. 1.Institut für Anorganische Chemie der Universität LeipzigLeipzigGermany
  2. 2.Department of Oral, Maxillofacial and Facial Plastic SurgeryUniversity of LeipzigLeipzigGermany
  3. 3.BiozentrumMartin-Luther-Universität Halle-WittenbergHalleGermany
  4. 4.Department of Chemistry, Institute of Chemistry, Technology and MetallurgyUniversity of BelgradeBelgradeSerbia
  5. 5.Departamento de Química Inorgánica y Analítica, E.S.C.E.T.Universidad Rey Juan CarlosMóstolesSpain

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