Original article Ferrocenyl and dicobalt hexacarbonyl chromones e New organometallics inducing oxidative stress and arresting human cancer cells in G2/M phase Konrad Kowalski a, * , Pawe1 Hikisz b , qukasz Szczupak a , Bruno Therrien c , Aneta Koceva-Chy1a b a Faculty of Chemistry, Department of Organic Chemistry, University of Lód z, Tamka 12, 91-403 Lód z, Poland b Department of Thermobiology, Faculty of Biology and Environmental Protection, University of Lód z, Pomorska 141/143, 90-236, Lód z, Poland c Institute of Chemistry, University of Neuchatel, Avenue de Bellevaux 51, CH-2000 Neuchatel, Switzerland article info Article history: Received 27 January 2014 Received in revised form 9 April 2014 Accepted 6 May 2014 Available online 9 May 2014 Keywords: Anticancer activity Ferrocene ROS Apoptosis Cell cycle Chromone abstract The straightforward syntheses of four new ferrocenyl and dicobalt hexacarbonyl chromones are pre- sented. The redox behavior of the novel metallo-chromones has been examined by cyclic voltammetry (CV), revealing a reversible behavior of the ferrocenyl groups, while the dicobalt hexacarbonyl derivatives show irreversible oxidation. The anticancer activity of the products has been evaluated against hepa- tocellular carcinoma (Hep G2), ERþ (MCF-7) and ER (MDA-MB-231) breast adenocarcinoma, and leukemic (CCRF-CEM) human cancer cell lines. The mechanism of action for the most active complexes has been investigated and it seems to involve oxidative stress and apoptosis induction. Moreover, the results show that the investigated metallo-chromones generate damage to DNA and arrest the cell cycle in G2/M phase. Ó 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction In the past decade, there has been continuous progress in the development of organometallic compounds for biological and medicinal applications. So far organometallic compounds have been used as luminescent probes for cellular imaging [1], as anti- cancer [2], antibacterial [3] and antiparasitic [4] agents, as IR-active tracers [5], and as models of active sites of enzymes [6]. This great interest in the biological function of organometallic complexes has resulted in a new branch of medicinal chemistry termed “bio- organometallic chemistry” [7]. The most common strategy utilized in searching for new bioactive organometallic compounds is based on conjugation or modification of the biomolecule with an organ- ometallic moiety. In this respect, the ferrocenyl group has evolved as the most intensively examined organometallic moiety [8], being conjugated to biogenic nucleobases [9], oligonucleotides [10], an- tibiotics [3], peptides [11], carbohydrates [12], biotin [13] and curcuminoids [14] to mention just a few examples. The dicobalt hexacarbonyl Co 2 (CO) 6 group, which is known to bind to alkynes, also has been utilized for biomolecule functionalization, however to a lesser extent than the ferrocenyl group. The Co 2 (CO) 6 conju- gates of aspirin were reported to exhibit significant anti-angiogenic properties in zebrafish embryos resulting from their interactions with the cyclooxygenase enzymes [15]. The Co 2 (CO) 6 derivatives of steroid hormones and antiepileptic drugs were utilized as IR-active tracers for the so-called carbonyl metallo immuno assay (CMIA) [16]. It was also reported that the coordination of the Co 2 (CO) 6 moiety to 5-alkynyl-2 0 -deoxyuridines [17a], properly designed imidazoles [17b], or other ligands [17c], triggers the cytotoxic ac- tivity of these compounds. The great number of biologically examined bioorganometallic compounds contrasts with the still limited knowledge on their cellular mechanisms of action. Initial reports by the groups of Köpf- Maier and Osella show that the oxidation state of the ferrocenyl moiety plays a crucial role in their cytotoxic effects [18]. Thus, it has been demonstrated that ferrocenium cations showed greater cytotoxic activity than their ferrocenyl counterparts [18c]. An oxidation-related mechanism of action has also been proposed for * Corresponding author. E-mail addresses: konkow@chemia.uni.lodz.pl, kondor15@wp.pl (K. Kowalski). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.05.023 0223-5234/Ó 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 81 (2014) 289e300