title: Cytotoxicity, apoptosis and study of the DNA-binding properties of bi- and tetranuclear gallium(III) complexes with heterocyclic thiolato ligands.
abstract: 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 [Me(2)Ga(S-imi)](2) (1), [Me(2)Ga(S-tet)](2) (2), [Me(2)Ga(S-ben)](2) (3) and [Me(2)Ga(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 1-4 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(NO(3))(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 IC(50) value of 5.49 ± 0.16 µM, very close to that of cisplatin (5.14 ± 0.12 µM). Complexes 1-4 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 IC(90) doses of 1-4 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 × 10(5), 4.44 × 10(5), 3.02 × 10(6) and 5.56 × 10(5) M(-1) for 1-4 were observed, however, no notable interaction with pBR322 plasmid DNA was detected.
authors.affiliation: Institut für Anorganische Chemie der Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gallego
authors.forename: Milena R
authors.initials: MR
authors.lastname: Kaluđerović
authors.forename: Harish
authors.initials: H
authors.lastname: Kommera
authors.forename: Reinhard
authors.initials: R
authors.lastname: Paschke
authors.forename: Evamarie
authors.initials: E
authors.lastname: Hey-Hawkins
authors.forename: Torsten W
authors.initials: TW
authors.lastname: Remmerbach
authors.forename: Goran N
authors.initials: GN
authors.lastname: Kaluđerović
authors.forename: Santiago
authors.initials: S
authors.lastname: Gómez-Ruiz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005708:Gallium / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D010957:Plasmids / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; D008024:Ligands; D013438:Sulfhydryl Compounds; D004247:DNA; D005708:Gallium; D020169:Caspases
references.citation: Eur J Med Chem. 2010 Feb;45(2):519-25
references.pmid: 19926362
references.citation: Arch Pharm (Weinheim). 2007 Mar;340(3):117-26
references.pmid: 17315259
references.citation: Met Based Drugs. 2000;7(1):33-47
references.pmid: 18475921
references.citation: Int J Rad Appl Instrum B. 1989;16(5):435-48
references.pmid: 2681083
references.citation: Chem Commun (Camb). 2001 Oct 7;(19):2016-7
references.pmid: 12240267
references.citation: J Inorg Biochem. 2002 Jul 25;91(1):298-305
references.pmid: 12121788
references.citation: Biochemistry. 1983 May 10;22(10):2406-14
references.pmid: 6860636
references.citation: J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
references.pmid: 2359136
references.citation: J Pharmacol Exp Ther. 2006 Apr;317(1):153-62
references.pmid: 16373528
references.citation: Int J Pharm. 2002 Oct 1;245(1-2):55-65
references.pmid: 12270242
references.citation: J Med Chem. 2004 Nov 18;47(24):5837-46
references.pmid: 15537341
references.citation: Anticancer Res. 2000 Mar-Apr;20(2A):955-8
references.pmid: 10810380
references.citation: J Inorg Biochem. 2006 Nov;100(11):1819-26
references.pmid: 16938349
references.citation: Chem Soc Rev. 2009 Feb;38(2):391-401
references.pmid: 19169456
references.citation: Dalton Trans. 2008 Jan 14;(2):183-94
references.pmid: 18097483
references.citation: J Inorg Biochem. 2003 Oct 1;97(2):215-20
references.pmid: 14512200
references.citation: Mol Cancer Ther. 2006 Nov;5(11):2834-43
references.pmid: 17121930
references.citation: Nucl Med Commun. 2004 Jan;25(1):49-53
references.pmid: 15061264
references.citation: Pharmacol Rev. 1998 Dec;50(4):665-82
references.pmid: 9860806
references.citation: Chem Soc Rev. 2008 Jun;37(6):1174-87
references.pmid: 18497930
references.citation: Int J Clin Pharmacol Ther. 2005 Dec;43(12):590-1
references.pmid: 16372529
references.citation: Biochem Pharmacol. 1992 Dec 15;44(12):2403-8
references.pmid: 1335254
references.citation: Curr Med Chem. 2006;13(11):1337-57
references.pmid: 16712474
references.citation: Inorg Chem. 2008 Dec 1;47(23):11284-93
references.pmid: 18986138
references.citation: Cancer Res. 1987 Aug 1;47(15):3929-34
references.pmid: 3475168
references.citation: Anticancer Res. 2006 May-Jun;26(3A):1739-43
references.pmid: 16827101
references.citation: Eur J Med Chem. 2009 May;44(5):1870-7
references.pmid: 19070402
references.citation: J Inorg Biochem. 2002 Jul 25;91(1):269-76
references.pmid: 12121785
references.citation: J Inorg Biochem. 1999 Jun 30;75(3):233-40
references.pmid: 10474207
references.citation: J Med Chem. 2008 Sep 11;51(17):5413-22
references.pmid: 18698754
references.citation: J Clin Invest. 1986 Dec;78(6):1538-46
references.pmid: 3465751
references.citation: J Inorg Biochem. 2007 Oct;101(10):1347-53
references.pmid: 17617464
references.citation: J Med Chem. 2007 Mar 22;50(6):1254-65
references.pmid: 17315858
references.citation: Met Ions Biol Syst. 2004;42:425-62
references.pmid: 15206110
references.citation: Curr Top Med Chem. 2004;4(15):1575-83
references.pmid: 15579097
references.citation: Angew Chem Int Ed Engl. 2006 Mar 27;45(14):2302-5
references.pmid: 16506300
references.citation: J Inorg Biochem. 2004 Dec;98(12):2099-106
references.pmid: 15541499
references.citation: Dalton Trans. 2007 Aug 28;(32):3474-82
references.pmid: 17680034
references.citation: Cancer Res. 2007 Oct 1;67(19):9258-65
references.pmid: 17909033
references.citation: Nucleic Acids Res. 1985 Sep 11;13(17):6017-34
references.pmid: 4047939
references.citation: Biochemistry. 1981 Jun 23;20(13):3744-8
references.pmid: 6268142