Synthesis, RNA-sequence and evaluation of anticancer efficacy of ruthenium(II) polypyridyl complexes toward HepG2 cells

Cancer has become one of the major diseases that endanger human health. Its incidence is getting higher and higher, and the mortality rate remains high [[1], [2], [3]]. Metastasis is defined as the ability of the primary tumor cells to invade and degrade tissue barriers at the surrounding sites and later to migrate to a distinct place to establish a distant lesion [[4], [5], [6]]. Metallodrugs as promising bioactive compounds in fighting against cancers have been extensively investigated over a century [7]. Althogh the platinum(II)-containing drugs (e.g. cisplatin, carboplatin, oxaliplatin) have been widely used as anticancer agents, their drawbacks, such as high levels of in vitro toxicity, drug resistance, constrain their clinical application [8], it is urgent to discover other transition metal-containing drugs as a alternative of platinum drugs. Ruthenium compounds have shown selective bioactivity and the ability to overcome the resistance that platinum-based therapeutics face, making them effective oncotherapeutic competitors in rational drug invention approaches [9]. Currently, two ruthenium complexes enter the clinical trials: sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (BOLD-100) [10] and [Ru(II)(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2‴-terthiophene)-imidazo[4,5-f][1,10]phenanthroline) (TLD-1433) [11]. In the past two decades, some Ru(II) polypyridyl complexes bearing 1,10-phenanthroline, 4,4′-dimethyl-2,2′-bipyridine and 2,2′-bipyridine exerted potent activities against numerous tumor cells [12]. Additionally, upon irradiation, the anticancer activity of the Ru(II) complexes can be significant enhanced, these complexes may be used as photodynamic therapy [[13], [14], [15], [16]]. In recent years, the studies on anticancer activity of Ru(II) complexes have been paid a great attention and a number of Ru(II) complexes show unique anticancer properties [[17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30]]. It is well known that there are several pathways in cell death including apoptosis, autophagy, and necrosis [31,32]. Apoptosis is programmed cell death and an ordered cellular process that occurs physiologically or pathologically. Wang et al. reported that near-IR-emitting and/or efficiently photodynamic water-soluble Ru(II) complexes [Ru(bpy)2(dtdpq)](ClO4)2 (bpy = 2,2′-bipyridine, dtdpq = 2,3-bis(thiophen-2-yl)pyrazino[2,3-f]-[1,10]phenanthroline) shows low cytotoxicity, however, upon irradiation, the complex exhibits high cytotoxic activity with a low IC50 value of 2.3 ± 0.3 μM against MCF-7 cells [33]. Chen et al. reported that the Ru(II) complexes can be effectively uptaken up by human cervical carcinoma (HeLa) cells. These complexes selectively kill cancer cell lines while mildly affect normal cells and induce autophagy-dependent cell apoptosis via mitochondrial dysfunction and reactive oxygen species (ROS) accumulation [34]. In our previous work [35], we found that iridium(III) complexes [Ir(ppy)2(TFPIP)](PF6) and [Ir(piq)2(TFPIP)](PF6) (TFPIP = 2-(4′-trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-imidazo[4,5-f][1,10]phenanthroline) show no cytotoxic activity against the selected cancer cells (IC50 > 100 μM). To explore the difference in the anticancer activity between Ru(II) and Ir(III) complexes, in this article, we synthesized four Ru(II) polypyridyl complexes: [Ru(dmbpy)2(TFBIP)](PF6)2 (dmbpy = 4,4′-dimethyl-2,2′-bipyridine) (Ru1), [Ru(bpy)2(TFBIP)](PF6)2 (bpy = 2,2′-bipyridine) (Ru2), [Ru(phen)2(TFBIP)](PF6)2 (phen = 1,10-phenanthroline) (Ru3) and [Ru(dmp)2(TFBIP)](PF6)2 (dmp = 2,9-dimethyl-1,10-phenanthroline) (Ru4) (Scheme 1). Our aim is to study whether these Ru(II) complexes can effectively inhibit the cancer cell growth and explore the anticancer mechanism, further compare the difference between Ru(II) and Ir(III) complexes so that we can obtain more information on anticancer activity of Ru(II) and Ir(III) complexes. The anticancer activity in vitro and in vivo of the four Ru(II) complexes against HepG2 cells was investigated in detail.

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