Research paperSynthesis and biological evaluation of organoselenium (NSAIDs-SeCN and SeCF3) derivatives as potential anticancer agents
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs widely used clinically to treat a variety of inflammatory conditions including pain associated with arthritis in the world [1,2]. On the other side, a growing body of studies addressed the chemo-preventive activities of NSAIDs, such as aspirin (ASA) and other NSAIDs can be used as chemo-preventive agents, especially in colorectal cancer (CRC) [3,4]. Other studies suggest that daily dosing of ASA decreases the risk of a great variety of cancer types, including lung, breast, skin, pancreas, and ovarian cancers [[5], [6], [7], [8]]. Additionally, a growing body of studies addressed the anticancer activities of NSAIDs [9,10], although their exact molecular mechanism has remained elusive.
Selenium (Se), a unique trace element plays a crucial role in human health and disease [11]. Organic selenium compounds with diverse functional groups, including selenoesters [12], selenocyanates [13,14], methylseleninic acid [15], isoselenocyanates [16], diselenides [17] and endocyclic selenium [18] have been reported to exhibit anticancer activity (Fig. 1). Among these compounds, organic selenocyanates have emerged as a promising candidate during the past two decades. The first selenocyanate described was the 1,4-phenylenebis(methylene)selenocyanate (p-XSC), which proved to be effective against prostate and oral carcinoma cells [19]. Recently, growing interest has been paid to bioactive organic trifluoromethyl sulfides (-SCF3) because of its unique properties which were brought by the trifluoromethylthio moiety including high lipophilicity (Hansch’s constant p = 1.44), metabolic stability and electron withdrawing effect [20,21]. In contrast to trifluoromethyl sulfides group, trifluoromethyl selenides (-SeCF3) group is suspected to have more lipophilic and stable group. However, the biological property of SeCF3 attached molecular is hardly documented at the moment: in the past few years, particular attention has focused on the synthetic methods to obtain trifluoromethylselenylated molecules [[22], [23], [24], [25], [26]].
In this report, considering the chemo-preventive effects of NSAIDs and the anticancer activity of organic selenium compounds, along with the reports that support the modification of NSAIDs scaffolds with Se functionalities [27,28], several NSAIDs-SeCN and NSAIDs-SeCF3 derivatives were designed with a general model consist of three essential fragments in their molecular: i) NSAIDs fragment; ii) electron donating group; iii)functional group bearing the Se atom (Fig. 2). The anticancer activity of the compounds was assessed using human cancer cell lines, SW480 (human colon adenocarcinoma cells), HeLa (human cervical cancer cells), A549 (human lung carcinoma cells), MCF-7 (human breast adenocarcinoma cells). Furthermore, the antioxidant potential of the compounds was investigated by employing DPPH, bleomycin-dependent DNA damage and GPx-like assays. Finally, docking studies were applied as a preliminary prediction tool to estimate the drugability of the prepared NSAIDs-Se hybrid compounds.
Section snippets
Chemistry
Herein we present the synthesis of novel families of NSAIDs-based selenoderivatives as potential anticancer agents: selenocyanates, trifluoromethyl selenides.
The synthesis of the NSAIDs-SeCN derivatives (2a-2j) was started from commercially available NSAIDs and 3-selenocyanatopropanamine hydrobromide (1) in the present of EDCI and HOBT as condensation agent, in DMF as solvent and under a nitrogen atmosphere (Scheme 1) [29].
Compound 1 was obtained by the nucleophilic substitution of -Br atom in
Conclusions
In summary, the present study reports the synthesis of new organoselenium derivatives including NSAIDs scaffolds and Se functionalities (-SeCN and -SeCF3), Compound 3h exhibited the most potent activity in MTT assay with remarkable anticancer activity against MCF-7 (2.8 μM at 72 h) and SW480 (3.3 μM at 48 h). Compounds 2h, 2i, 3h and 3i were selected to verify if organic selenides can induce apoptosis in MCF-7 cells by modulating the expression of the Bcl-2, IL-2 and caspase-3 molecular
Materials
All chemical reagents for the synthesis of the compounds were perchased from Macklin (Shanghai, China) or TCI (Shanghai, China) and used without further purification unless stated otherwise. TLCs were performed on aluminium pre-coated sheets (E. Merck Silica gel 60 F254). Melting points (uncorrected) were recorded on an Electrothermal apparatus. 1H (400 MHz), 13C (100 MHz) NMR and 19F (376 MHz) spectra were recorded at 25 °C on a Bruker Avance 400 MHz spectrometer with 5 mm PABBO probe.
Statistical analysis
MTT data were given as mean ± SD of three independent experiments, graphs and curve fitting were using origin Version 8.0 (OriginLab Corporation, Northampton, USA). P value less than 0.05 was considered statistically significant.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This investigation was made possible through the financial support of National Natural Science Foundation of China (Grant No:21302065) and Shenzhen Fushan Biological Technology Co., Ltd.
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