Two oxovanadium(IV) complexes of [VO(msatsc)(phen)], (1) (msatsc = methoxylsalicylaldehyde thiosemicarbazone, phen = phenanthroline) and its novel derivative [VO (4-chlorosatsc)(phen)], (2) (4-chlorosatsc = 4-chlorosalicylaldehyde thiosemicarbazone), have been synthesized and characterized by elemental analysis, IR, ES-MS, 1H NMR, and magnetic susceptibility measurements. Their antitumor effects on BEL-7402, HUH-7, and HepG2 cells were studied by MTT assay. The antitumor biological mechanism of these two complexes was studied in BEL-7402 cells by cell cycle analysis, Hoechst 33342 staining, Annexin V-FITC/PI assay, and detection of mitochondrial membrane potential (ΔΨm). The results showed that the growth of cancer cells was inhibited significantly, and complexes 1 and 2 mainly caused in BEL-7402 cells G0/G1 cell cycle arrest and induced apoptosis. Both 1 and 2 decreased significantly the ΔΨm, causing the depolarization of the mitochondrial membrane. Complex 2 showed greater antitumor efficiency than that of complex 1. 1. Introduction Schiff bases are an important class of ligands because such ligands and their transition metal complexes have a variety of applications including biological, clinical, and analytical applications [1]. The development of the field of bioinorganic chemistry has increased the interest in Schiff base complexes, because it has been recognized that N and S atoms play a key role in the coordination of transition metals at the active sites of many metallobiomolecules [2, 3]. The importance of metal ions in biological systems is well established. One of the most interesting features of metal-coordinated systems is the concerted spatial arrangement of the ligands around the metal ion [3–5]. Among the various transition metal ions used in pharmacological studies, Vanadium and its derivatives have been reported to display different biological effects including antitumor, antimicrobial, antihyperlipidemia, antihypertension, antiobesity, enhancement of oxygen affinity of hemoglobin and myoglobin, insulin-enhancing effects, and so on [6–8]. Vanadium complexes have also been explored for lowering of glucose levels [9–12], diuretic and natriuretic effects, antitumor activity against chemical carcinogenesis in animals and malignant cell lines (in vitro). Much effort has been done for vanadyl species coordinated to organic ligands on the research of their mimetic effects in hopes of developing vanadodrugs [13–15]. Because V(IV) complexes have no charge, they are perceived to be candidates for easy bioabsorption. On the other hand,
References
[1]
X. G. Ran, L. Y. Wang, D. R. Cao, Y. C. Lin, and J. Hao, “Synthesis, characterization and in vitro biological activity of cobalt(II), copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and D,L-selenomethionine,” Applied Organometallic Chemistry, vol. 25, no. 1, pp. 9–15, 2011.
[2]
P. K. Sasmal, A. K. Patra, M. Nethaji, and A. R. Chakravarty, “DNA cleavage by new oxovanadium(IV) complexes of N-salicylidene α-amino acids and phenanthroline bases in the photodynamic therapy window,” Inorganic Chemistry, vol. 46, no. 26, pp. 11112–11121, 2007.
[3]
J. Vanco, O. Svajlenova, E. Racianska, J. Muselik, and J. Valentova, “Antiradical activity of different copper(II) Schiff base complexes and their effect on alloxan-induced diabetes,” Journal of Trace Elements in Medicine and Biology, vol. 18, no. 2, pp. 155–162, 2004.
[4]
J. A. Obaleye, J. F. Adediji, and M. A. Adebayo, “Synthesis and biological activities on metal complexes of 2,5-diamino-1,3,4-thiadiazole derived from semicarbazide hydrochloride,” Molecules, vol. 16, no. 7, pp. 5861–5874, 2011.
[5]
X. Tai, X. Yin, Q. Chen, and M. Tan, “Synthesis of some transition metal complexes of a novel Schiff base ligand derived from 2,2′-bis(p-methoxyphenylamine) and salicylicaldehyde,” Molecules, vol. 8, no. 5, pp. 439–443, 2003.
[6]
P. Noblía, E. J. Baran, L. Otero et al., “New vanadium(V) complexes with salicylaldehyde semicarbazone derivatives: synthesis, characterization, and in vitro insulin-mimetic activity—crystal structure of [ (salicylaldehyde semicarbazone)],” European Journal of Inorganic Chemistry, vol. 2004, no. 2, pp. 322–328, 2004.
[7]
P. Pattanayak, J. L. Pratihar, D. Patra et al., “Synthesis, structure and reactivity of azosalophen complexes of vanadium(IV): studies on cytotoxic properties,” Dalton Transactions, no. 31, pp. 6220–6230, 2009.
[8]
A. Messerschmidt and R. Wever, “X-ray structure of a vanadium-containing enzyme: chloroperoxidase from the fungus Curvularia inaequalis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 1, pp. 392–399, 1996.
[9]
D. C. Crans and A. S. Tracey, “The chemistry of vanadium in aqueous and nonaqueous solution,” ACS Symposium Series, vol. 711, pp. 2–29, 1998.
[10]
R. Liasko, T. A. Kabanos, S. Karkabounas et al., “Beneficial effects of a vanadium complex with cysteine, administered at low doses on benzo(α) pyrene-induced leiomyosarcomas in wistar rats,” Anticancer Research, vol. 18, no. 5A, pp. 3609–3613, 1998.
[11]
P. Prasad, P. K. Sasmal, R. Majumdar, R. R. Dighe, and A. R. Chakravarty, “Photocytotoxicity and near-IR light DNA cleavage activity of oxovanadium(IV) Schiff base complexes having phenanthroline bases,” Inorganica Chimica Acta, vol. 363, no. 12, pp. 2743–2751, 2010.
[12]
P. K. Sasmal, S. Saha, R. Majumdar, R. R. Dighe, and A. R. Chakravarty, “Photocytotoxic oxovanadium(IV) complexes showing light-induced DNA and protein cleavage activity,” Inorganic Chemistry, vol. 49, no. 3, pp. 849–859, 2010.
[13]
A. A. Holder, “Inorganic pharmaceuticals,” Annual Reports on the Progress of Chemistry A, vol. 107, pp. 359–378, 2011.
[14]
Y. Sun, L. E. Joyce, N. M. Dickson, and C. Turro, “DNA photocleavage by an osmium(ii) complex in the PDT window,” Chemical Communications, vol. 46, no. 36, pp. 6759–6761, 2010.
[15]
S. P. Dash, S. Pasayat, S. H. R. Dash, S. Das, R. J. Butcher, and R. Dinda, “Oxovanadium(V) complexes incorporating tridentate aroylhydrazoneoximes: synthesis, characterizations and antibacterial activity,” Polyhedron, vol. 31, no. 1, pp. 524–529, 2012.
[16]
S. A. Patil, V. H. Naik, A. D. Kulkarni, U. Kamble, G. B. Bagihalli, and P. S. Badami, “DNA cleavage, in vitro antimicrobial and electrochemical studies of Co(II), Ni(II), and Cu(II) complexes with m-substituted thiosemicarbazide Schiff bases,” Journal of Coordination Chemistry, vol. 63, no. 4, pp. 688–699, 2010.
[17]
O. S. Frankfurt and A. Krishan, “Apoptosis-based drug screening and detection of selective toxicity to cancer cells,” Anti-Cancer Drugs, vol. 14, no. 7, pp. 555–561, 2003.
[18]
H. L. Xu, X. F. Yu, S. C. Qu et al., “Anti-proliferative effect of Juglone from Juglans mandshurica Maxim on human leukemia cell HL-60 by inducing apoptosis through the mitochondria-dependent pathway,” European Journal of Pharmacology, vol. 645, no. 1–3, pp. 14–22, 2010.
[19]
J.-Z. Lu, Y.-F. Du, H.-W. Guo, J. Jiang, X.-D. Zeng, and L.-Q. Zang, “Two oxovanadium complexes incorporating thiosemicarbazones: synthesis, characterization, and DNA-binding studies,” Journal of Coordination Chemistry, vol. 64, no. 7, pp. 1229–1239, 2011.
[20]
Y. F. Du, J. Z. Lu, H. W. Guo, and J. Jiang, “DNA binding and photocleavage properties of two mixed-ligand oxovanadium complexes,” Transition Metal Chemistry, vol. 35, pp. 859–864, 2010.
[21]
J. Z. Lu, X.D. Zeng, H. W. Guo et al., “Synthesis and characterization of unsymmetrical oxidovanadium complexes: DNA-binding, cleavage studies and antitumor activities,” Journal of Inorganic Biochemistry, vol. 112, pp. 39–48, 2012.
[22]
I. Kostova, “Titanium and vanadium complexes as anticancer agents,” Anti-Cancer Agents in Medicinal Chemistry, vol. 9, no. 8, pp. 827–842, 2009.
[23]
S. K. S. Hazari, J. Kopf, D. Palit, S. Rakshit, and D. Rehder, “Oxidovanadium(IV) complexes containing ligands derived from dithiocarbazates—models for the interaction of VO2+ with thiofunctional ligands,” Inorganica Chimica Acta, vol. 362, no. 4, pp. 1343–1347, 2009.
[24]
B. Khera, A. K. Sharma, and N. K. Kaushik, “Bis(indenyl)titanium(IV) and zirconium(IV) complexes of monofunctional bidentate salicylidimines,” Polyhedron, vol. 2, no. 11, pp. 1177–1180, 1983.
[25]
M. Tümer, H. K？ksal, S. Serin, and M. D？g？rak, “Antimicrobial activity studies of mononuclear and binuclear mixed-ligand copper(II) complexes derived from Schiff base ligands and 1,10-phenanthroline,” Transition Metal Chemistry, vol. 24, no. 1, pp. 13–17, 1998.
[26]
M. Tümer, C. ？elik, H. S. K. ksal, and S. Serin, “Transition metal complexes of bidentate Schiff base ligands,” Transition Metal Chemistry, vol. 24, no. 5, pp. 525–532, 1999.
[27]
S. K. Dutta, S. B. Kumar, S. Bhattacharyya, E. R. T. Tiekink, and M. Chaudhury, “Intramolecular electron transfer in (BzImH)[(LOV)2O] (H2L = S-methyl 3-((2-Hydroxyphenyl)methyl)dithiocarbazate): a novel μ-Oxo dinuclear oxovanadium(IV/V) compound with a trapped-valence (V2O3)3+ core,” Inorganic Chemistry, vol. 36, no. 22, p. 4954, 1997.
[28]
A. A. Nejo, G. A. Kolawole, A. R. Opoku, J. Wolowska, and P. O'Brien, “Synthesis, characterization and preliminary insulin-enhancing studies of symmetrical tetradentate Schiff base complexes of oxovanadium(IV),” Inorganica Chimica Acta, vol. 362, no. 11, pp. 3993–4001, 2009.
[29]
R. L. Farmer and F. L. Urbach, “Stereochemistry and electronic structure of oxovanadium(IV) chelates with tetradentate Schiff base ligands derived from 1,3-diamines,” Inorganic Chemistry, vol. 13, no. 3, pp. 587–592, 1974.
[30]
V. B. Arion, V. C. Kravtsov, R. Goddard et al., “Oxovanadium(IV) and oxovanadium(IV)-barium(II) complexes with heterotopic macrocyclic ligands based on isothiosemicarbazide,” Inorganica Chimica Acta, vol. 317, no. 1-2, pp. 33–44, 2001.
[31]
X. G. Ran, L. Y. Wang, D. R. Cao, Y. C. Lin, and J. Hao, “Synthesis, characterization and in vitro biological activity of cobalt(II), copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and D,L-selenomethionine,” Applied Organometallic Chemistry, vol. 25, no. 1, pp. 9–13, 2011.
[32]
B. Banik, P. K. Sasmal, S. Roy, R. Majumdar, R. R. Dighe, and A. R. Chakravarty, “Terpyridine oxovanadium(IV) complexes of phenanthroline bases for cellular imaging and photocytotoxicity in HeLa cells,” European Journal of Inorganic Chemistry, no. 9, pp. 1425–1435, 2011.
[33]
R. W. Johnstone, A. A. Ruefli, and S. W. Lowe, “Apoptosis: a link between cancer genetics and chemotherapy,” Cell, vol. 108, no. 2, pp. 153–164, 2002.
[34]
W. Hu and J. J. Kavanagh, “Anticancer therapy targeting the apoptotic pathway,” The Lancet Oncology, vol. 4, no. 12, pp. 721–729, 2003.
[35]
J. D. Ly, D. R. Grubb, and A. Lawen, “The mitochondrial membrane potential (ΔΨ？m) in apoptosis; an update,” Apoptosis, vol. 8, no. 2, pp. 115–128, 2003.
[36]
S. H. Kaufmann and M. O. Hengartner, “Programmed cell death: alive and well in the new millennium,” Trends in Cell Biology, vol. 11, no. 12, pp. 526–534, 2001.
[37]
C. B. Thompson, “Apoptosis in the pathogenesis and treatment of disease,” Science, vol. 267, no. 5203, pp. 1456–1462, 1995.
[38]
S. J. Martin and D. R. Green, “Apoptosis and cancer: the failure of controls on cell death and cell survival,” Critical Reviews in Oncology/Hematology, vol. 18, no. 2, pp. 137–153, 1995.
[39]
I. Vermes, C. Haanen, H. Steffens-Nakken, and C. Reutelingsperger, “A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V,” Journal of Immunological Methods, vol. 184, no. 1, pp. 39–51, 1995.
[40]
Y. J. Liu and C. H. Zeng, “Synthesis of ruthenium(II) complexes and characterization of their cytotoxicity in vitro, apoptosis, DNA-binding and antioxidant activity,” European Journal of Medicinal Chemistry, vol. 45, no. 7, pp. 3087–3095, 2010.
[41]
G. Klopman, “Chemical reactivity and the concept of charge- and frontier-controlled reactions,” Journal of the American Chemical Society, vol. 90, no. 2, pp. 223–229, 1968.
[42]
A. Klein, P. Holko, J. Ligeza, and A. M. Kordowiak, “Sodium orthovanadate affects growth of some human epithelial cancer cells (A549, HTB44, DU145),” Folia Biologica, vol. 56, no. 3-4, pp. 115–121, 2008.
[43]
M. O'Connor, A. Kellett, M. McCann et al., “Copper(II) complexes of salicylic acid combining superoxide dismutase mimetic properties with DNA binding and cleaving capabilities display promising chemotherapeutic potential with fast acting in vitro cytotoxicity against cisplatin sensitive and resistant cancer cell lines,” Journal of Medicinal Chemistry, vol. 55, no. 5, pp. 1957–1968, 2012.
[44]
R. Kim, “Recent advances in understanding the cell death pathways activated by anticancer therapy,” Cancer, vol. 103, no. 8, pp. 1551–1558, 2005.
[45]
R. S. Ray, B. Rana, B. Swami, V. Venu, and M. Chatterjee, “Vanadium mediated apoptosis and cell cycle arrest in MCF7 cell line,” Chemico-Biological Interactions, vol. 163, no. 3, pp. 239–247, 2006.
[46]
J. Benítez, L. Becco, I. Correia et al., “Vanadium polypyridyl compounds as potential antiparasitic and antitumoral agents: new achievements,” Journal of Inorganic Biochemistry, vol. 105, no. 2, pp. 303–312, 2011.
[47]
A. Bishayee, A. Waghray, M. A. Patel, and M. Chatterjee, “Vanadium in the detection, prevention and treatment of cancer: the in vivo evidence,” Cancer Letters, vol. 294, no. 1, pp. 1–12, 2010.
