Synthesis, properties, antitumor and antibacterial activity of new Pt(II) and Pd(II) complexes with 2,2 0 -dithiobis(benzothiazole) ligand Simona Rubino ⇑ , Rosalia Busà, Alessandro Attanzio, Rosa Alduina, Vita Di Stefano, Maria Assunta Girasolo, Santino Orecchio, Luisa Tesoriere Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF), Università di Palermo, Viale delle Scienze pad. 16, Parco d’Orleans, 90128 Palermo, Italy article info Article history: Received 15 December 2016 Revised 23 February 2017 Accepted 24 February 2017 Available online 9 March 2017 Keywords: Platinum complex Palladium complex Heterocyclic nitrogen ligand Anticancer activity Antimicrobial activity abstract Mono- and binuclear Pt(II) and Pd(II) complexes with 2,2 0 -dithiobis(benzothiazole) (DTBTA) ligand are reported. [Pt(DTBTA)(DMSO)Cl]Cl∙CHCl 3 (1) and [Pd 2 (m-Cl) 2 (DTBTA) 2 ]Cl 2 (2) have been synthesized and structurally characterized by elemental analysis, IR, 1 H and 13 C NMR spectroscopy, MS spectrometry and the content of platinum and palladium was determined using a flame atomic spectrometer. Two dif- ferent coordination modes of 1 and 2 complexes were found; in both complexes, the coordination of Pt(II) and Pd(II) ions involves the N(3) atoms of the ligand but the binuclear complex 2, is a cis-chloro-bridged palladium complex. Evaluation of their in vitro antitumor activity against two human tumor cell lines human breast cancer (MCF-7) and hepatocellular carcinoma (HepG2); and their antimicrobial activity against Escherichia coli and Kokuria rhizophila was performed. Only complex 1 showed a dose- and time-dependent cytotoxic activity against the two tumor cell lines, associated to apoptosis and accumu- lation of treated cells in G0/G1 phase of cell cycle, while both 1 and 2 exhibited antimicrobial activity with complex 1 much more potent. The study on intracellular uptake in both MCF-7 and HepG2 cell lines revealed that only platinum of complex 1 is present inside the cells, suggesting a different mode of action of the two compounds. This was also in agreement with the results obtained for the antitumor and antibacterial activity. Ó 2017 Elsevier Ltd. All rights reserved. 1. Introduction The development of new antimicrobial and anticancer thera- peutic agents is one of the fundamental goals in medicinal chem- istry. In this field the chemistry of heterocyclic compounds and of their complexes with Pt(II) and Pd(II) metallic ions is one of the leading lines of investigations in both inorganic and organic chemistry. There are vast numbers of pharmacologically active heterocyclic compounds, many of which are regularly in clinical use. Five membered heterocyclic compounds containing Nitrogen, Sulphur and Oxygen have occupied enormous significance in the field of drug discovery process. 1 Among pharmacologically impor- tant heterocyclic compounds, the Benzothiazole (BTA) and its derivatives are the most important heterocyclic compounds, which are common and integral feature of natural products and pharmaceutical agents and show a variety of pharmacological properties. BTA analogs offer a high degree of structural diversity that has proven to be useful for the search of new therapeutic agents that exert a wide range of biological activities such as anti- cancer, antimicrobial, anticonvulsant, antiviral, antitubercular, antimalarial, anthelmintic, analgesic, anti-inflammatory, antidia- betic and fungicidal activity. 2 The BTA is a heterocyclic compound in which benzene ring is fused to 4,5-positions of thiazole ring, is completely planar, and is potentially ambidentate with N and S available to coordination when it is used as ligand in metal ion complexes. The thiazole core is present in many biologically rele- vant molecules, which are in therapeutic use, such as Sulfathiazole (antimicrobial drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug), Tiazofurin (antineoplastic agent), Meloxicam http://dx.doi.org/10.1016/j.bmc.2017.02.067 0968-0896/Ó 2017 Elsevier Ltd. All rights reserved. Abbreviations: AO, Acridine Orange; BTA, Benzothiazole; DTBTA, 2,2 0 -dithiobis (benzothiazole); DTT, 1, 4-Dithiothreitol; DMF, dimethylformamide; DMSO, dimethylsulfoxide; EB, Ethidium Bromide; EDTA, Ethylenediaminetetraacetic acid; FACS, Fluorescence-Activated Cell Sorting; FBS, Fetal Bovine Serum; FITC, Fluores- cein isothiocyanate; MS, Mass Spectrometry; HESI, Heated Electrospray Ionization; MIC, Minimal inhibitory concentration; MTT, 3-(4,5-dimethyl-2-thiazolyl)bromide- 2,5-diphenyl-2H-tetrazolium; PBS, phosphate buffer; PI, Propidium Iodide; PS, phosphatidylserine; RPMI, Roswell Park Memorial Institute; TBE, Tris/Borate/EDTA; TLC, Thin Layer Chromatography; TMS, tetramethylsilane. ⇑ Corresponding author. Tel.: +39-091-23897972; fax: +39-091-6577270. E-mail address: simona.rubino@unipa.it (S. Rubino). Bioorganic & Medicinal Chemistry 25 (2017) 2378–2386 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc