The triphenyltin(VI) complexes of NSAIDs and derivatives. Synthesis, crystal structure and antiproliferative activity. Potent anticancer agents Vaso Dokorou, Alexandra Primikiri, Dimitra Kovala-Demertzi ⁎ Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110, Ioannina, Greece abstract article info Article history: Received 5 May 2010 Received in revised form 8 October 2010 Accepted 8 October 2010 Available online 16 October 2010 Keywords: Triphenyltin(IV) Complexes Crystal structure Spectral studies Antiproliferative activity The novel triphenyltin(IV) esters of flufenamic acid (1), Hflu, [Ph 3 Sn(flu)] (2), and of [2-(2,3-dichlorophe- nylamino)benzoic acid] (3), Hdcpa, [Ph 3 Sn(dcpa)] (4) have been structurally characterized by means of vibrational and 1 H, 13 C NMR spectroscopic studies. The crystal and molecular structures of [SnPh 3 (dcpa) (DMSO)] 4a are described. The molecular structure of 4a reveals that the Sn atom has a distorted trigonal bipyramidal coordination geometry with equatorial phenyl groups and the carboxylate and dimethylsulf- oxide oxygen atoms occupying axial positions. The crystal structure of 4a is self-assembled by C–H—π and π–π stacking interactions. The in vitro cytotoxic activity of 1–4 and of the related non-steroidal anti-inflammatory drugs, NSAIDs, [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa (5), [Ph 3 Sn(dmpa)] (6), [2-(2,3- dimethylphenylamino)benzoic acid], mefenamic acid, Hmef (7) and [Ph 3 Sn(mef)] (8) has been evaluated against the cancer cell lines MCF-7, T-24, A-549 and L-929. The ligands exhibited very poor cytotoxic activity against the four cancer cell lines. Complex 6 exhibits the highest activity and selectivity against A-549 and MCF-7 cancer cell lines and complex 8 the highest activity and selectivity against T-24 cancer cell line. The cytotoxic results indicate that coupling of Hdmpa and Hmef with R 3 Sn(IV) metal center results in complexes with important biological properties and remarkable cytotoxic activity, since they display IC 50 values in a μΜ range better to that of the antitumor drug cis-platin. Complexes 6 and 8 are considered as excellent antitumor compounds and the results of this study represent the discovery of triphenyltin(IV)esters as a potential novel class of anticancer agents. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Flufenamic acid [2-(3-trifluorophenylamino)benzoic acid], Hflu(1) (Scheme 1), belongs to the class of non-steroidal anti-inflammatory drugs, NSAIDs, which are clinically used against a wide range of acute and chronic disorders. The therapeutic activity of these analgesics is believed to be due to their ability to inhibit the biosynthesis of prostaglandins by competitive interaction with the cyclooxygenase– arachidonic acid complex or by radical quenching agents that interfere with the initiation of the cyclooxygenase reaction [1]. Flufenamic acid was found to inhibit the proliferation and migration of human aortic smooth muscle cells (HASMCs) in vitro [2]. The crystal structure of Hflu [3] and of flufenamic acid with prostaglandin D (2) 11-ketoreductase (AKR1C3) has been reported [4]. Flufenamic, mefenamic and meclofenamic belong to the class of fenamates. [2-(2,3-dichlorophenylamino)benzoic acid], Hdcpa (3) (Scheme 1) and [2-(2,6-dimethylphenylamino)benzoic acid], Hdmpa (5) chemically resemble to fenamates in clinical use. Hdcpa (3) was found to inhibit by 56.6% on triiodothyronine (T3) uptake by H4 hepatocytes and octanol–water partition coefficient (logP) was found to be 5.457 [5]. The anti-inflammatory activity of Hdcpa (3) was measured by the anti- UV-erythema test and the minimum effective dose (MED) was found to be 3.1 mg/kg, while for flufenamic and tolfenamic the MED value was found to be 3.3 and 5.3 mg/kg, respectively [6]. Crystal structures of dimeric tetraorganodistannoxanes of flufenamic, mefenamic, meclo- fenac, Hdcpa and Hmpa have been reported [7–10]. The crystal structures of triphenyltin(IV) esters of mefenamic acid, meclofenamic (9) and Hdmpa (5) have been also reported and were tested for antimycobacter- ial activity against Mycobacterium tuberculosis H37Rv. These triphenyltin esters were found to be very good anti-tuberculosis agents [11–14]. The coordination chemistry of NSAIDs has been studied by several groups worldwide. Some complexes have increased pharmaceutical or biological activity with respect to the drug, or are interesting from a purely chemical point of view [10,11,15]. The complex formation with specific metals may improve the activity towards certain diseases and hopefully may increase the activity spectrum. The combination of two or more different species into the same compound may bring to a multitherapeutic agent which can be expanded by the synergic action of the metal residue once the coordination compound dissociates inside the target tissue. Metal complexes have been successfully applied in the treatment of numerous human diseases. Very important progress in medicinal Journal of Inorganic Biochemistry 105 (2011) 195–201 ⁎ Corresponding author. Tel.: +30 2651008425; fax: +30 2651008786. E-mail address: dkovala@cc.uoi.gr (D. Kovala-Demertzi). 0162-0134/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2010.10.008 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio