Original articleSynthesis, crystal structure and antitumor effect of a novel copper(II) complex bearing zoledronic acid derivative
Graphical abstract
A novel copper(II) complex bearing zoledronic acid derivative with effective antitumor activity and low hepatotoxicity was designed and evaluated.
Introduction
In the last decades, extensive researches have proposed a growing number of antineoplastic agents [1], [2], [3]. Among them, transition metal-based complexes represent an important class of chemotherapeutics that has been used extensively for clinical treatments. Platinum complexes as typical chemotherapeutic agents have received remarkable attention since first being introduced to treat the disease almost four decades ago, such as cisplatin, carboplatin and oxaliplatin [4], [5]. Though many of these drugs are quite effective in treating primary cancers, some drugs fail to remain effective once the tumor has become metastatic [6]. Moreover, due to lack of specificity, platinum-based anticancer chemotherapies are often associated with various severe side effects including nephrotoxicity, hepatotoxicity, ototoxicity, neurotoxicity, gastrointestinal toxicity, etc. The intrinsic and acquired resistances possessed by various cancers also limit the clinical efficacy of these drugs [5], [7]. Therefore, it is essential to design novel metal complexes with less toxicity and better specificity to overcome these adverse effects [8], [9], [10].
Up to now, a plenty of new compounds featuring alternative metals in preclinical studies have been proved to be promising antitumor pharmaceuticals, such as copper [11], which is an essential metal ion involved in several highly conserved biochemical processes [12]. Copper is taken up by the cell through human copper transporter 1 (hCTR1) and delivered by chaperones to its intracellular destinations [13], [14], [15]. The ability of iterating between two oxidation states (+1 and +2) is one of the key features, which has been exploited by organisms throughout evolution [16]. In recent years, copper complexes were designed and preliminarily screened to show promise as both antiproliferative and antimetastatic agents [16], [17], [18], [19], [20], [21]. For instance, Raja et al. demonstrated the antioxidative and cytotoxic activity of a series of copper complexes with 2-oxo-1,2-dihydroquinoline-3-carbaldehyde derivatives, which showed significant radical scavenging activity and effective cytotoxicity against cancerous cell lines such as human cervical cancer cells (HeLa), human laryngeal epithelial carcinoma cells (HEp-2), human liver carcinoma cells (HepG2), and human skin cancer cells (A431) [17], [18]. Castle et al. reported a series of copper complexes of semicarbazones, which possessed fascinating biological activities and potential applications as anticancer agents as well as diagnostic and therapeutic radiopharmaceuticals [19], [20], [21]. These results stimulated wide interests in the search of effective antitumor copper complexes.
The chemical feature of the ligands has been recognized to be the main determinant of biological activities of complexes [22], which can (i) modulate the permeability through the cell membranes by tuning their lipophilic character, (ii) direct the toxicities of the metals toward specific intracellular targets, and (iii) exhibit an intrinsic cytotoxic activity when they dissociate from the center metals. Diphosphonates (DPs) are a class of drugs with P–C–P backbone structure, showing high affinity for bone mineral and other calcified tissues, and used as therapeutic agents against hypercalcemia of malignancy (caused by several tumors), skeletal metastases, Paget's disease, and postmenopausal osteoporosis [23]. In addition to being prescribed as drugs, DPs can serve as drug targeting and delivery vehicles for therapeutic and diagnostic applications [24], [25], [26]. Compared with other molecules, DPs have more advantages for targeted delivery of therapeutic agents to bone because their binding affinity and biological activity can be tuned by changing their R1 and R2 substituents [27]. Therefore, combination of the bifunctional diphosphonate and the copper moiety can ideally promote the specific accumulation of the drug in the bone-related tumors or metastases with significant improvement in the chemotherapy efficacy and reduction in the systemic toxicity.
Zoledronic acid (ZL), a typical third-generation diphosphonate, is the most potent and widely used in the clinical treatment of skeletal diseases [28]. Due to the multidentate chelating ability, ZL is known to form stable chelates with many metals and envisaged as a possible carrier moiety to develop metal-based radiopharmaceuticals with great potential applications in the nuclear medicine [29], [30], [31], [32], [33], [34]. Also it exhibits multiply bridging properties to combine with diverse transition metal ions to form versatile architectures with promising applications in the material science [35], [36], [37], [38]. In a continuing effort to find metal-based compounds with high anticancer activity and low toxicity, we herein report two novel copper complexes based on ZL and its derivative IPrDP (Scheme 1), {[Cu3(ZL)2(H2O)6]·6H2O}n (1) (ZL = 1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid) and [Cu(IPrDP)2]·3H2O (2) (IPrDP = 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid). This is the first case of copper complex containing the diphosphonate ligand reported as an anticancer agent. The present work includes the synthesis, structural characterization, antitumor activity, hepatotoxicity, action mechanism, and DNA binding studies.
Section snippets
Materials and methods
All chemicals were purchased as reagent grade and used without further purification. CDDP was purchased from Shandong BoYuan pharmaceutical Co., Ltd. The diphosphonic acid ligand ZL and IPrDP were prepared according to the method as described in our previous work [32]. The human cancer cell lines U2OS (human osteosarcoma cell line), A549 (human lung cancer cell line), HCT116 (human colon carcinoma cell line), MDA-MB-231 (human breast cancer cell line) and HepG2 (human liver carcinoma cell line)
Synthesis, IR spectroscopy and crystal structure
Scheme 2 shows the formation of complexes 1 and 2 with ZL and IPrDP as ligands respectively. They were fully characterized by the elemental analysis, IR spectroscopy and X-ray crystallography. The IR spectra exhibit both complicated and important peaks in the range of 900–1300 cm−1 for the complexes 1–2 and the corresponding ligands ZL and IPrDP (Fig. S1). For the ligand ZL, the strong absorptions at 1178 and 1094 cm−1 are ascribed to the PO stretching vibrations, and the absorptions at 1056
Conclusion
In summary, two novel copper(II) complexes based on ZL and its derivative IPrDP were designed and synthesized, {[Cu3(ZL)2(H2O)6]·6H2O}n (1) and [Cu(IPrDP)2]·3H2O (2). Due to different coordination modes in the homologous diphosphonates, 1-D polymer of 1 and mononuclear complex of 2 were formed respectively. In both complexes, extensive hydrogen-bonding interactions are found among the phosphonate oxygen atoms, hydroxy groups, protonated imidazole groups and water molecules. Complex 2 shows
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (21371082, 21001055), Natural Science Foundation of Jiangsu Province (BK20141102), Key Medical Talent Project of Jiangsu Province (RC2011097) and Public Service Platform for Science and Technology Infrastructure Construction Project of Jiangsu Province (BM2012066).
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