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  • These reports have gradually established G quadruplex bindin


    These reports have gradually established G-quadruplex binding small molecules as promising anti-cancer therapeutic agents. Besides the stabilization of G-quadruplex structures, some of these molecules also serve as diagnostic probes and sensors for G-quadruplexes in vitro and in vivo. Of these, Thioflavin T (ThT, Fig. 1), a well-known dye known for its binding to proteins, has been found to be an excellent stabilizer and inducer of human telomeric G-quadruplex DNA and its binding has also been reported with other G-quadruplexes [[67], [68], [69], [70], [71], [72], [73], [74], [75], [76]]. Several studies have suggested that binding of ThT to G-quadruplexes results in a huge increase in fluorescence and that they can also be used as G-quadruplex specific gel staining agents [68]. These findings have led to further explorations of ThT core containing ligands as new scaffolds of G-quadruplex targeting [77]. However, barring human telomeric DNA G-quadruplex [71], binding studies with other G-quadruplexes are few and their interaction details are limited. In this article, we report interaction of ThT with a well-established G-quadruplex target within the human promoter region of the c-Myc gene. We have used a variety of spectroscopic methods (UV–Visible, fluorescence and circular dichroism) to study ThT interaction with the c-Myc G-quadruplex DNA sequences and compared its binding to DNA duplexes. The spectroscopic studies presented in this article shed light on thermal stability effects, mode of binding and insights into future design of ThT based ligands for targeting G-quadruplex sequences.
    Results and Discussion Spectroscopic studies of nucleic acid-small molecule binding have aided significantly in understanding the nature of interactions and defining the mode of binding of nucleic acids. Several molecules, beginning with classical examples of minor groove binders such as Hoechst 33258, netropsin and intercalators such as ethidium bromide, have helped tremendously in defining the observables for characterization of small molecule-nucleic orphan receptor interaction [[81], [82], [83], [84]]. The spectroscopic signatures of nucleic acid binding thus aid us greatly in designing the lead compounds and determining the efficacy of the new scaffolds at the specified target. In the present study, the focus of our experiments was to understand (a) the thermal stability effects of ThT binding to c-Myc G-quadruplex DNA (b) fluorescence behavior of ThT in the presence of the G-quadruplex DNA (c) understanding the mode of interaction of c-Myc G-quadruplex DNA binding (d) determination of binding ratio of ThT complexation to c-Myc G-quadruplex DNA and (e) compare these results with the molecular docking experiments. Wherever applicable, we compared the binding of ThT with the duplex DNA sequences of similar length as in c-Myc G-quadruplex; that are either AT or GC rich or both to understand the effects of purine or pyrimidine richness in DNA duplex binding. The DNA sequences studied are outlined in Table 1.
    Introduction Homeobox genes were first identified in Drosophila due to their function of regulating morphogenesis and cell differentiation, and their mutations leading to the growth of body parts in inappropriate contexts. In mammals, homeobox genes consist of a large family of over 200 similar and well conserved genes that play essential roles during embryonic development. HOX genes are a subset of homeobox genes. While homeobox genes are mostly dispersed throughout the whole genome, mammalian HOX gene families are organized as distinct clusters on different chromosomes. The human genome contains four unlinked HOX gene complexes consisting of 39 genes including the HOXA cluster with 11 genes on chromosome 7, the HOXB cluster with 10 genes on chromosome 17, the HOXC cluster with 9 genes on chromosome 12, and the HOXD cluster with 9 genes on chromosome 2 [1,2]. Homeobox proteins act as transcription factors to regulate the expression of lineage-specific genes. Many of them modulate the expression of genes involved in cell cycle progression and thus their abnormal expression may contribute to oncogenesis.