In summary two new flexible amine functionalized quinolinium

In summary, two new flexible amine-functionalized quinolinium derivatives with far-red region emitting were prepared. The shorter-chain fatty amine side chain in the scaffold of was found to be a more promising G-quadruplex DNA fluorescent probe, suggesting the amine side group plays an important role in controlling the compound for the selective recognition. expressed hypochromicity followed by bathochromic shift effect of its trovafloxacin australia spectra and significant fluorescence enhancements upon binding with G-quadruplex DNAs, while showed insignificant changes upon interactions with duplex DNA structures. The detailed interactions of with G-quadruplex DNAs using various experiments and molecular docking were illustrated. The results demonstrate that interacts with G-quadruplex structures mainly by the groove binding mode and exhibits higher binding affinity to parallel G-quadruplex structures. Additionally, the CD experiments display is able to sense G-quadruple structures without affecting their topologies. Further chemical modifications in the scaffold are currently underway for developing more selective G-quadruplex probes. Acknowledgements This work was financially supported by Technical Research Program for Chongqing Education Commission (KJ1600916, KJ1600931), Chongqing Research Program of Basic Research and Frontier Technology (No. cstc2016jcyjA0508, cstc2018jcyjAX0518), China Postdoctoral Science Foundation funded project (2016T90851 and 2017M611704), General Program of Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (17KJB150009).
Introduction Guanine (G)-rich sequences have been shown to fold into a special secondary structure named G-quadruplex which is paired by Hoogsteen bonding and kept by charge coordination with monovalent cations. Computational analyses have identified that there are about 370,000 sequences with the potential to form G-quadruplex in the human genome [1]. However, a recent research using high-resolution sequencing–based methods identified that the number of regions for quadruplex formation reaches 716,310, far beyond our imagination [2]. G-quadruplexes are earlier found in telomere ends of eurkaryotic genomes, which play a central role in inhibiting telomerase activity [3,4]. Subsequent researches confirm that G-quadruplexes are also prevalent in many important gene promoters, and some of them have been revealed to participate in transcriptional regulation of genes [5,6]. These important functions in cellular physiology have made G-quadruplex promising as a possible therapeutic target. In spite of this, how those processes are carefully orchestrated through these atypical DNA structures remains unclear. In recent years, emerging evidence shows that the biological functions of G-quadruplex structures are intimately related with the binding of some specific proteins [[7], [8], [9], [10], [11], [12], [13]]. Take the splice variant of mammalian heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2*) as an example, it is proven to actively unfold telomeric G-quadruplex DNA and substantially enhance the catalytic activity of telomerase, leading to telomere elongation in vivo [7]. Besides hnRNP A2*, replication protein A (RPA), unwinding protein 1 (UP1), and human Pif1 are also demonstrated to unfold G-quadruplex structures [[8], [9], [10], [11], [12], [13]]. On the contrary, nucleolin, a multifunctional phosphoprotein, was found to facilitate the formation and increase the stability of the c-myc G-quadruplex structure, resulting in a decrease in c-myc promoter activity [14]. Although the effect of these proteins on G-quadruplex structures is different, all the interactions between proteins and G-quadruplexes have potential implications in silencing or activating their corresponding physiological processes. For this reason, the specific binding of proteins to G-quadruplexes has become an important issue that deserves great attention. IGF-1, a protein playing crucial role in normal growth and development, is known as a significant modulator of cell growth, differentiation, and invasiveness. The high levels of IGF-1 are found to be closely related to tumorigenesis [[15], [16], [17]]. In vitro studies have clearly shown the relationship between IGF-1 levels and the expression of several oncogenes including Bcl-2, c-myc, and c-fos [18,19]. It is proven that the promoters of these oncogenes can fold to form the G-quadruplex structures involved in the transcription of oncogenes [[20], [21], [22], [23]]. We suppose that IGF-1 may specifically bind with the G-quadruplex structures and potentially serve as a G-quadruplex-binding protein. To this end, herein, the specific interaction between IGF-1 and variant G-quadruplex structures was first measured by using FIRM (Fig. 1), fluorescence, and SPR spectroscopy. We found that IGF-1 binds to G-quadruplex structures, especially the G-quadruplex structure with parallel topology, with higher affinity and selectivity when compared with other single-stranded and duplex DNA structures. Besides, we also demonstrated that the interaction between IGF-1 and G-quadruplexes could be efficiently weakened by the quadruplex-specific ligands such as TMPyP4 and PDS. (See Scheme 1.)