Iron-salophen complexes involving azole-derived ligands: A new group of compounds with high-level and broad-spectrum in vitro antitumor activity Ján Vančo a , Zdeněk Šindelář a , Zdeněk Dvořák b , Zdeněk Trávníček a, ⁎ a Regional Centre of Advanced Technologies and Materials, Department of Inorganic Chemistry, Faculty of Science, Palacký University in Olomouc, 17. listopadu 12, CZ-771 46 Olomouc, Czech Republic b Regional Centre of Advanced Technologies and Materials, Department of Cell Biology and Genetics, Faculty of Science, Palacký University in Olomouc, Šlechtitelů 11, CZ-783 71 Olomouc, Czech Republic abstract article info Article history: Received 6 May 2014 Received in revised form 7 October 2014 Accepted 7 October 2014 Available online xxxx Keywords: Iron complexes Schiff base Salophen In vitro cytotoxicity Antitumor activity A series of iron(II/III) salophen (salph) complexes involving monodentate azole-derived ligands, having the composition [Fe II (salph)(HL1)] (1) and [Fe III (salph)(L)] (2–6), where HL1 = imidazole, L = 1,2,4-triazol-1-ido (L2), benzo[d][1,2,3]triazol-1-ido (L3), 5-aminotetrazol-1-ido (L4), 5-phenyltetrazol-1-ido (L5), and 5- methyltetrazol-1-ido (L6) ligand, was prepared and characterized by elemental analyses, infrared, Mössbauer and X-ray photolelectron spectroscopy, magnetic data and electrospray-ionization mass spectrometry. X-ray structure of 1 revealed a distorted square–pyramidal geometry in the vicinity of the iron(II) atom. The complexes were evaluated for their in vitro antitumor activity against the panel of six human cancer cell lines (HOS, MCF7, A549, HeLa, A2780 and G-361) and were found to be highly cytotoxic, showing the best IC 50 value of 58 nM for [Fe III (salph)(L6)] (6) against the ovarian carcinoma A2780 cell line, being 200-times more effective than cisplatin. In vitro cytotoxicity of complexes 1–6 on primary culture of human hepatocytes and calf-thymus DNA (CT-DNA) binding studies using the fluorescence titration were also performed. © 2014 Elsevier Inc. All rights reserved. 1. Introduction According to the World Health Statistics, promulgated by the WHO [1], the neoplastic diseases belong among the most abundant in terms of morbidity as well as mortality, especially in highly-developed coun- tries. Therefore, the search for new, more effective and safer drugs to be used in therapeutic practice of these diseases represents a strong so- cial imperative. It is a well-documented fact that the regulation of iron blood levels in the target tissues plays an important role in the cancer cell proliferation [2,3]. In addition to the antiproliferative effect of iron blood level depri- vation, it was found that the chelation of “free” (non-chelated) iron leads to antiangiogenic action [4–6] and thus it can influence a key stage of tumor invasion and metastasis. On the other hand, it has been proved on several occasions that low-molecular Fe(II/III) complexes with ligands derived from Schiff bases act by the different mechanisms, usually based on the direct interactions with DNA and other biomole- cules, and therefore cause the inhibition of growth of various human cancer cells in vitro [7–9]. A number of iron complexes, involving the salophen chelating li- gand (hereafter within this text abbreviated as salph) or its alkoxy-, hydroxy-, alkyl-, or trihalomethyl-derivatives, was identified to possess the antitumor activity during the last decade [10–16]. These complexes of the general formula [Fe(salph)(L) x ], where x = 1–2, and L x stands for any additional monodentate ligand(s), usually show the square– pyramidal or distorted octahedral geometry (see Fig. 1), in which the equatorial positions are occupied by the O,N,N,O′-donor set of the salph ligand and the apical position are usually occupied by O-ligands (e.g. water or alcohol), S-ligands (e.g. thiolato), halogenido ligands (usually the chlorido ligand), and N-ligands (e.g. involving one or two heterocyclic ligands such as 4,4′-bipyridine [17], benzimidazole, imid- azole, pyridine, pyrazine, μ-{2-(((4H-1,2,4-triazol-4-yl)imino)methyl) phenolato-κO:N1} ligand [17–25], aniline-derivatives [26], or small li- gands like nitrosyl [27], azido [21], and isothiocyanato-κN [21]). The in vitro antitumor activity of several of the above-mentioned complexes, e.g. [Fe III (salph)Cl], was identified to be quite extraordinary, reaching up to 10-times the effectiveness of cisplatin [13], and some of these complexes (e.g. [Fe III (3,3′-MeO-salph)Cl(H 2 O)], where 3,3′- MeO-salphH 2 stands for the Schiff base derived from ortho-vanillin and 1,2-phenylenediamine [15]) were also able to overcome the resistance of specific human cancer cell lines towards the platinum- containing drugs [15,28–31]. Journal of Inorganic Biochemistry 142 (2015) 92–100 ⁎ Corresponding author. Tel.: +420 585634352; fax: +420 585634954. E-mail address: zdenek.travnicek@upol.cz (Z. Trávníček). http://dx.doi.org/10.1016/j.jinorgbio.2014.10.002 0162-0134/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio