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    • Also a large number of small

    2021-09-26

    Also a large number of small molecules are potent G-quadruplex ligands that exhibit anti-proliferative activity in cells [39,48]. Several small molecules, for example cyclic naphthalene diimide derivative [43], cationic porphyrins [2,[49], [50], [51], [52]] and pentaheteroaryls [53], quinacridines [52], PIPER [52], quarfloxin [54], methylene blue derivatives [55], fonsecin B [56], berberine derivatives [57], carbazoles [58,59], quindoline derivatives [6,60], platinum [[61], [62], [63], [64]] and cobalt [65] complexes, bisquinoline-pyrrole oligoamide [66], indolylmethyleneindanones [67], amido phthalocyanines [68], bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10-phenanthroline [69], or perylene and coronene derivatives [70], have been identified to bind and stabilize G-quadruplex structures in the c-myc promoter region. Carbazole derivatives are very interesting compounds because of their biological and photophysical properties. They are able to target DNA structures, some of which have potential for development into anticancer drugs [71,72]. Imidazole and triazole groups, as well as carbazole-based compounds, play an important role in medicinal chemistry, because many of them exhibit various biological properties - antibacterial, antifungal, antiinflammatory, antiparasitic, anticancer, antiviral [[73], [74], [75]]. In this study we present the stability and interaction of three carbazole ligands with G-quadruplex formed by a sequence corresponding to Pu22 region of c-myc NHE III1. Pu22 is the modified mycPu22, the wild-type 22-mer G-rich sequence of the c-myc NHE III1 that forms a parallel intramolecular G-quadruplex in the physiological K+ solution. This structure was resolved by NMR method after modification of mycPu22 at the 14 and 23 positions (G-to-T substitutions) [6].
    Materials and methods
    Results and discussion
    Conclusions The main aim of this work was to investigate the interaction of three carbazole ligands, differing in substituent at nitrogen Ursodiol of carbazole, with G-quadruplex formed by the DNA sequence derived from the NHE III1 region of c-myc oncogene (Pu22). The binding of compounds 1–3 was investigated by UV–Vis spectrophotometry, fluorescence, CD spectroscopy, and molecular modeling. The results have shown that all ligands have ability to stabilize the intramolecular G-quadruplex Pu22 and interact by the same binding mode. The spectrophotometric titration results have shown a trend towards large hypochromicity at lower G4/ligand ratios followed by hyperchromic effect at higher G4 concentrations, which indicates the presence of more than one binding mode. Being weakly fluorescent in aqueous solution, these vinylic derivatives of carbazole display strong fluorescence enhancement when bound to c-myc G-quadruplex. CD melting studies indicate that the ligands have the ability to form and stabilize the c-myc G-quadruplex structure. The experimental results indicate that the ligand 1 shows the strongest interactions with the tested c-myc G-quadruplex, however, the strength of interaction with ligand 2 is almost at the same level. This is consistent with the results of molecular modeling, where ligand 2 possessed the best stabilization properties of G-quadruplex. However, the simple correlation between energy values and complex stability was not observed, which indicates that strong interactions between ligand and G-quadruplex do not necessarily result in better stability of the system. Altogether, the data indicate that carbazole skeleton is an attractive scaffold for further structural modifications.
    Acknowledgments This research was cofinancially supported by the Foundation for Polish Science within the PARENT-BRIDGE programme (grant number POMOST-2011-3/3). SH is a UCL Career Excellence Fellow.
    Introduction Aptamers, deemed to the competitive affinity reagents, are single-stranded oligonucleotides mainly obtained by in vitro selection process [1,2]. Enormous species such as small molecules, proteins, viruses and cells could be specifically recognized by aptamers [[3], [4], [5]]. And the compelling features of aptamers lie in broad aspects, such as high specificity for recognition, well designability for constructing different probes and detection platforms, high stability and reusability for robust detection, and low-cost for widely used assays [6,7]. These unique characteristics emphasize the importance of their utilization for constructing bioassays for food analysis, clinical diagnosis, as well as environmental monitoring [[8], [9], [10], [11]].