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  • Ru II complexes have been

    2022-05-21

    Ru(II) complexes have been reported to be both duplex and G-quadruplex structure stabilizers, and potent anticancer agents [[11], [12], [13], [14]]. Barton, Norden, as well as Ji groups have provided detailed information about recognition and reactions of classical duplex DNA by Ru complexes [[47], [48], [49], [50]]. Over the past 15 years, a rational approach to design Ru complexes that 891 can selectively interact with G-quadruplex DNA has emerged. For example, a series of Ru(II) complexes synthesized by our lab, have shown remarkable G-quadruplex formation and stabilization ability [[51], [52], [53], [54]]. Rickling et al. studied the interactions of the dinuclear [(tap)2Ru(tpac)Ru-(tap)2]4+ complex with the human telomeric sequence of d(T2AG3)4 (tap = 1,4,5,8‑tetraazaphenanthrene, tpac = tetrapyridoacridine). They found that the complex can damage these sequences by intramolecular photocrosslinking [55]. Piraux et al. reported the new Ru(II) complexes based on a novel dipyrazino [2,3‑a:2′,3′‑h]phenazine ligand (dph), and these complexes behave as selective probes for G-quadruplex [56]. Besides, a number of Ru based on anticancer agents targeting G-quadruplex, such as, cis‑[RuCl2(S‑(‑)‑FOA)(DMSO)2] [57], [Ru(bpy)2(icip)]2+, [Ru‑(bpy)2(pdppz)]2+ and [Ru(bpy)2(tactp)]2+ [58], (η6‑C6H6)Ru(p‑XPIP)Cl]Cl [59], [(bpy)2Ru(bpibp)Ru(bpy)2](ClO4)4 and [(phen)2Ru (bpibp)Ru(phen)2](ClO4)4 [60] have been reported too FOA = 4‑(2,3‑dihydroxypropyl)‑formamide oxoaporphine, bpy = 2,2′‑bipyridine, icip = 2‑(indeno[2,1‑b]chromen‑6‑yl)‑1H‑imidazo[4,5‑f][1,10]phenanthroline, pdppz = phenanthro[4,5‑abc]dipyrido‑[3,2‑h:2′,3′‑j]phenazine, tactp = 4,5,9,18‑tetraazachryseno[9,10‑b]‑triphenylene, X = Cl, PIP = 2‑phenylimidazole[4,5f][1,10]phenanthroline, bpibp = 4,4′‑bis (1,10‑phenanthroline‑[5,6‑d] imidazole‑2‑yl)‑biphenyl, phen = 1,10‑phenanthroline . From the previous studies, ideal G-quadruplex binder should show a high level of selectivity between quadruplex and duplex DNA when attempting to develop a powerful anticancer drug. However, anthracyclines daunomycin and doxorubicin that are two widely used anticancer drugs [61], exhibit non-selective binding properties between quadruplex and duplex DNA [62], which play an important role in their chemotherapeutic effects [63]. Experimental evidence suggests that intercalation of an anthracyclines into DNA duplex structure playing critical roles in suppressing tumor growth [64]. Besides, these drugs can also interact with telomeric DNA quadruplexes and induce cancer cell senescence and apoptosis [65]. These results hint some anticancer drugs might bind both G-quadruplex and duplex DNA. Ascididemin (ASC) is a pentacyclic marine pyridoacridine alkaloid, which extracts from the marine animal tunicates and sponges [[66], [67], [68]]. Due to its significant cytotoxic properties against a series of tumor cell lines, including multidrug resistant cancer cells, ASC has received great interest [69]. It has been reported that, ASC intercalates into DNA base pairs, especially at GC-rich sequences and inhibits topoisomerase II enzyme [[66], [67], [68], [69]]. Bonnard and co-workers reported that, DNA binding is the likely reason of ASC cytotoxic activity [69]. We conceive that Ru(II) complexes of ASC ligands would be a potent G-quadruplex DNA binders, as they would possess a planar aromatic ligands, which can stack on the flat surface of a terminal G-quartet in quadruplex structures. In this study, we have combined three Ru(II) polypyridyl complexes containing N‑N‑chelating ligands, such as [Ru(L)2Cl2] [L = bpy, phen and tatp (1,4,8,9‑tetra‑aza‑triphenylene) with ASC ligands to generate three novel complexes named [Ru(bpy)2ASC]2+ (1), [Ru(phen)2ASC]2+ (2) and [Ru(tatp)2ASC]2+ (3), the synthetic route to complexes 1–3 are shown in Scheme 1. In order to evaluate the quadruplex binding affinity, selectivity and structure-activity relationships of ruthenium complexes 1–3 and ASC with different DNA structures, a series of spectroscopic analysis and molecular docking studies have been carried out. In this experiment three different quadruplex sequences, including Htelo (human telomeric DNA), c-myc and c-kit that all can form G-quadruplex in the presence of K+ condition and duplex DNA (ds26) were selected to study.