Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio In vitro and in silico study of the biological activity of manganese(III) inverse-[9-MC-3]-metallacrowns and manganese(II) complexes with the anti-inflammatory drugs diclofenac or indomethacin George D. Geromichalos a,b , Alketa Tarushi a , Konstantinos Lafazanis b,c , Anastasia A. Pantazaki c , Dimitris P. Kessissoglou a , George Psomas a, ⁎ a Laboratory of Inorganic Chemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece b Cell Culture, Molecular Modeling and Drug Design Lab, Symeonidion Research Center, Theagenion Cancer Hospital, Thessaloniki GR-54007, Greece c Laboratory of Biochemistry, Faculty of Chemistry, Aristotle University of Thessaloniki, GR-54124 Thessaloniki, Greece ARTICLE INFO Keywords: Manganese compounds Cytotoxicity DNA-binding Albumin-binding In silico modeling ABSTRACT In the present contribution, the biological properties of four manganese complexes with the non-steroidal anti- inflammatory drugs sodium diclofenac (Nadicl) or indomethacin (Hindo) in the presence or absence of salicy- laldoxime (Η 2 sao), i.e. [Μn 6 (O) 2 (dicl) 2 (sao) 6 (CH 3 OH) 6 ] 1, [Μn 6 (O) 2 (indo) 2 (sao) 6 (H 2 O) 4 ], 2, [Μn (dicl) 2 (CH 3 OH) 4 ], 3, and [Μn(indo) 2 (CH 3 OH) 4 ], 4 are presented. More specifically, the in vitro cytotoxic effects of the complexes were evaluated against three cancer cell lines (HeLa, MCF-7 and A549 cells) as well as their combinatory activity with the well-known chemotherapeutic drugs irinotecan, cisplatin, paclitaxel and 5- fluorouracil. The biological activity of the complexes was investigated in vitro by studying their affinity to calf- thymus DNA and their binding towards bovine or human serum albumin (HSA). Molecular docking simulations on the crystal structure of HSA and human estrogen receptor alpha (hERa) were employed in order to study in silico the ability of the studied complexes to bind to these proteins. 1. Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic, anti-inflammatory and antipyretic medicaments [1], al- though they may induce renal and gastrointestinal side-effects, such as ulceration and hemorrhage [2,3]. The main mode of action of the NSAIDs is the inhibition of the production of prostaglandins which is mediated by the enzymes cyclooxygenase-1 and cyclooxygenase-2 [4,5]. Additionally, the NSAIDs have presented synergetic activity with diverse antitumor drugs [5] and have also exhibited themselves note- worthy antitumor activity inducing the cell death of cancer cell lines [6–8]. Within this context, DNA is also a biological target of the NSAIDs and their compounds and the study of this interaction is an initial ap- proach of potential anti-inflammatory and anticancer activity [9–11]. Indomethacin (Hindo, Fig. 1(A)) and sodium diclofenac (Nadicl, Fig. 1(B)) are commonly used anti-inflammatory, analgesic and anti- pyretic agents that belong to the phenylalkanoic acid derivatives used as NSAIDs [12–14]. Indomethacin and its copper(II) complex are clinically used mainly in the treatment of acute inflammation [14]. In the literature, the structures of copper(II) [15–18], nickel(II) [19] and tin(IV) complexes [20] with indomethacin have been found. The so- dium salt of diclofenac is used in the treatment of rheumatoid arthritis and osteoarthritis [12]. Considering the metal-diclofenac complexes, reports on the Cu(II) [21–24], Mn(II) [25,26], Cd(II) [27], Sn(IV) [28] and Ni(II) [29] complexes have been found in the literature. Since the discovery of cytotoxic properties of cisplatin by Prof. Rosenberg fifty years ago [30], the research concerning metallo- pharmaceuticals has been mainly focused on the platinum complexes which have been proven to be among the most effective chemother- apeutic agents, despite their known side-effects [31–35]. In parallel, mononuclear Ru complexes such as NAMI-A ([HIm][trans-RuCl 4 (dmso-S) (Im)], Im = imidazole), KP1019 (trans-[Ru(III)Cl 4 (1H-indazole) 2 ]) and those of RAPTA (Ru(II)-arene 1,3,5-triaza-7-phosphaadamantane) series have been thoroughly investigated for the cytotoxic efficacy [36,37]. In addition, polynuclear metal-based drugs have been also examined for their potential cytotoxicity [38–41], e.g. the platinum chemotherapeutic AP5346. Furthermore, there are many recent reports in the literature regarding the cytotoxic properties of diverse polynuclear or polymeric complexes with diverse metal ions, such as Mn(II) [42], Co(II) [43], Cu (II) [44], Zn(II) [45,46], Sn(IV) [47] and Ru(II) [48]. https://doi.org/10.1016/j.jinorgbio.2018.07.007 Received 24 November 2017; Received in revised form 2 May 2018; Accepted 18 July 2018 ⁎ Corresponding author. E-mail address: gepsomas@chem.auth.gr (G. Psomas). Journal of Inorganic Biochemistry 187 (2018) 41–55 Available online 21 July 2018 0162-0134/ © 2018 Elsevier Inc. All rights reserved. T