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  • tgf beta receptor 1 br Experimental br Results and


    Results and discussion
    Conclusion In conclusion, four bisnaphthalimides have been investigated for their potential G-quadruplex binding. The compounds 3a, 3b and 5b display high affinity for telomeric and oncogenic G-quadruplexes. On the other hand, 5a only show high affinity for the c-kit and telomeric quadruplex (Ka > 106 M−1), and interact with c-myc quadruplex and duplex CT DNA weakly. Molecular docking analysis suggests that 3a, 3b, 5a and 5b interact with the groove and/or loop of the G-quadruplex through hydrogen bonding. Fluorescence intensity of 3a and 3b is enhanced dramatically in the presence of G-quadruplex. Fluorescence imaging further indicate that 3a and 3b can readily enter A549 cells. These compounds efficiently inhibit the growth of A549 cancer cell lines with low cytotoxicity toward noncancerous cell MRC-5. These results indicate that the bisnaphthalimide with G-quadruplex binding properties may possess tumor cell-selective cytotoxic activity, which is helpful to design novel naphthalimide anticancer agent.
    Acknowledgements This research is supported by the Natural Science Foundation of Shaanxi Province (2018JM2019, 2016JM2013), the National Natural Science Foundation of China (21073143), and the NPU Foundation for Graduate Innovation (ZZ2017192).
    Introduction Metallodrugs plays an important role in cancer treatment [1]. The well-known metal based chemotherapy drug is cisplatin. But its severe side effects and drug resistance limited its application [2]. In order to overcome the drawbacks of currently used chemotherapy and find more clinically efficient anticancer drugs, several tgf beta receptor 1 of alternative metal based compounds were developed [1]. Among these metal complexes, ruthenium (Ru) complexes stood out, especially because of its physiologically accessible oxidation states and lower toxicity toward healthy tissue probably due to the ability of Ru to mimicking iron in binding to biomolecules [[3], [4], [5]]. A number of Ru complexes showed promising anticancer activities and three of them, NAMI-A (imidazolium‑trans‑DMSO‑imidazole‑tetrachlororuthenate), KP1019 indazolium trans‑[tetrachlorobis(1H‑indazole)ruthenate(III)] and (N)KP1339 sodium trans‑[tetrachloridobis(1H‑indazole)ruthenate(III)] have successfully entered in clinical trials [[6], [7], [8]]. Binding of small molecules with DNA has been studied extensively since DNA is the material of inherence and controls the structure and function of cells [9,10]. In this respect Ru(II) complexes have attracted a great deal of attention due to their strong DNA-binding and potential anticancer activities [[11], [12], [13], [14]]. Furthermore, DNA is highly polymorphic and can adopt a variety of different helical conformations [15,16] (B [17], A [18], and Z [19]) as well as unusual structures (hairpins [20], cruciform [21], triplexes [22], i-motif [23] and G-quadruplexes [24]). It has been suggested that these secondary DNA structures could be involved in the regulation tgf beta receptor 1 of several key biological processes. Among these different non-canonical DNA motifs, DNA G-quadruplex are probably the most extensively studied [25,26]. Such structures are made up of G-quartet subunits, where four coplanar guanines (G) are linked together by Hoogsteen hydrogen bonds [[27], [28], [29], [30], [31]]. G-quadruplex structures are highly dynamic and polymorphic too, which can fold into different topologies such as, parallel, antiparallel and hybrid depending on the base sequences, loop connectives and cations [32]. During the last decade, G-quadruplex has emerged from being a structural curiosity observed in vitro, to being recognized as a possible nucleic acid based mechanism for regulating multiple biological processes in vivo [33,34]. There is great evidence that G-quadruplexes play an overarching role in biology. G-quadruplexes are found throughout the human genome [35] and in mRNA [36], especially in gene promoters and telomeres. For example, human telomeric DNAs are made up of double stranded TTAGGG repeats and ends 3′ single stranded overhang [[37], [38], [39], [40]]. The folding of the single stranded 3′ overhang into G-quadruplex makes the telomerase lose substrate, inhibits telomerase activity (which is up regulated >85% cancer cells), and prevents telomere extension, thus induces tumor cells senescence and apoptosis [[40], [41], [42], [43], [44]]. Owing to the strong relations between telomerase and cancers, great efforts have been devoted to develop the anticancer strategy based on small molecules that could target and stabilize G-quadruplex structure, with the aim of inhibit telomerase and induce cancer cell death. In addition, G-quadruplex formation in oncogene promoter regions such as c-kit (oncogene c-kit promoter sequences), c-myc (cellular-myelocytomatosis viral oncogene), bcl-2 (b-cell CLL/lymphoma 2) and K-ras (kirsten rat sarcoma viral oncogene) has been proposed to function as a transcriptional controller of these genes [45], gene expression can be suppressed by G-quadruplex stabilizing ligands [46].