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  • Introduction G quadruplexes are therapeutically important no

    2022-08-05

    Introduction G-quadruplexes are therapeutically important non-canonical nucleic UNC669 receptor structures that are formed by a planar assembly of four guanines, termed G-tetrads (Fig. 1), in the guanine rich regions of genome [[1], [2], [3]]. As it is getting increasingly established, several life forms including humans, bacteria, viruses, and plants have myriad putative G-quadruplex forming regions distributed throughout the genome in coding, non-coding and in untranslated regions of mRNA at both 3′ and 5′ ends [[4], [5], [6], [7], [8], [9]]. In humans, G-quadruplexes have been detected in live cells in chromosomal regions which are rich in guanines [10,11]. Since G-quadruplex formation leads to inhibition of telomerase activity [[12], [13], [14], [15]] and impedes transcriptional activity [[16], [17], [18]], they are considered as a promising target of anti-cancer drug design. Recent reports showing the presence of G-quadruplex structures in several spliced RNA sequences have further established their role in the regulatory events of cell cycle and have augmented their importance in current drug design efforts [19,20]. Genome-wide analysis of human DNA has shown that G-quadruplexes are widely distributed throughout human genome [21]; especially in the promoter regions of several protooncogenes such as VEGF, KRAS, c-Myc, c-Kit, KRAS and at the telomeric ends. Of these, c-Myc gene has been studied in detail with respect to a G-quadruplex forming motif found in the nuclease hypersensitivity element (NHE) III [[22], [23], [24], [25]]. c-Myc is a regulatory protooncogene that controls the expression of almost 15% of total genes in humans. It codes for the various transcription factors resulting in the regulation of numerous biological processes like cell proliferation, cell differentiation, apoptosis and stem cell self-renewal. The over-expression of the c-Myc promoter gene is often associated with inhibition of cellular differentiation and potentiation of cellular proliferation, leading to carcinomas of cervix, breast, colon, osteosarcoma, glioblastoma [[26], [27], [28]]. The NHE-III (nuclease hypersensitivity element) in the c-Myc gene leads to the formation of parallel G-quadruplex structures that acts as a silencer element and is responsible for transcriptional repression [29,30]. A 27-nucleotide G-rich sequence of c-Myc NHE III has been widely studied for its solution structure. NMR based structure of the 27mer oligonucleotide in potassium salt has been found to be polymorphic with the major structural component forming 1:2:1 loop arrangement [24,31]. There is increasing evidence that the c-Myc regulation can be greatly influenced by the presence of G-quadruplex structures, which are, in turn, influenced by the chemical agents that stabilize them. Recently, a small molecule APTO-253 (a phenanthroline derivative), has emerged as a potential drug candidate which is involved in the c-Myc down-regulation [32]. Moreover, several reports have indicated that G-quadruplex forming human telomeric sequence can also be used towards the development of new anticancer agents by inhibiting the functions of telomerase [[33], [34], [35], [36], [37], [38], [39], [40]]. Together, these results have shown that specific targeting of G-quadruplexes with small molecules can lead to both new drugs as well as in sensing G-quadruplexes in vivo which could help in deciphering its functions in transcriptional and translational events. Numerous small molecules representing various structural classes have been reported to bind to a variety of G-quadruplexes belonging to different topologies [39,[41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57]]. A common ligand structural feature that has emerged out of these explorations is the requirement of fused aromatic rings with heteroatoms to maximize overlap with the G-tetrads. Additionally, flexible charged moieties have also been found to enhance binding to the G-quadruplexes by reaching out to their grooves [37,53,54,58,59]. On these lines, many small molecules belonging to a variety of core skeletons have been reported to have significant interactions with the c-Myc G-quadruplex with selectivity over other telomeric DNA quadruplexes and duplex DNAs in some cases; as well as down-regulation of expression of c-Myc gene [60]. In particular, quindoline, acridone, carbazole, phenanthroline, anilinoquinazoline and its derivatives have shown remarkable binding to c-Myc G-quadruplex sequences with varying degrees of anticancer properties [[61], [62], [63], [64]]. There are also some reports on water-soluble dyes (Tetraazaperopyrene and carbazole cyanine dyes) that act as a strong c-Myc G-quadruplex binding fluorescent probes [65,66].