A study on a telo21 G-quadruplex DNA specific binding ligand: enhancing the molecular recognition ability via the amino group interactions

Abstract

A symmetric ligand is synthesized composed of a core N-methylpyridinium scaffold and two parasubstituted benzyl groups through a flexible ethylene bridge to form a novel three-ring-conjugated system. The ligand system was found to have only weak background fluorescent signal in aqueous or physiological conditions and exhibited strong fluorescent signal enhancement targeting at telo21 Gquadruplex structure rather than other types of nucleic acids. The comparison study with two terminal groups (-N(CH 3 ) 2 versus -SCH 3 ) indicates that the stimulated signal enhancement of specific binding is probably attributed to the hydrogen-bonding interactions through the amino groups in the G-quartets.The docking result illuminates the experimental observation that the ligand system showed only weak fluorescent signals in aqueous or physiological conditions while exhibiting a strong fluorescent signal upon binding to the telo21 G-quadruplex structure (binding energy: À6.2 kcal mol À1 ).

Structurally diverse G-quadruplexes as the noncanonical nucleic acid drug target for live cell imaging and antibacterial study

“…In an attempt to probe the crucial factors in rational design of G4-selective ligands, our group has developed several ligand systems. We found that, apart from adopting a planar core molecular fragment to construct G4-ligands, the overall molecular size, 116 symmetry, 117,118 flexibility, 83 and the character of terminal groups [119][120][121][122] may affect the in vitro selectivity of the ligand toward G4-structures against RNA, single-and double-stranded DNA. Our study suggests that some smallsized molecular scaffolds including benzothiazole-benzofuroquinolinium, 123,124 benzothiazole-indolium, 125 1-methylquinolinium, 126 thiazole orange 81,84,127 and benzo[e]indole 128 are good molecular fragments for the design of fluorescent G4-ligands to achieve high discrimination ability, sensitivity and quantum yield targeting certain types of G4s for in vitro sensing and live cell imaging.…”

Synthesis of fluorescent G-quadruplex DNA binding ligands for the comparison of terminal group effects in molecular interaction: Phenol versus methoxybenzene

“…[30,31] Some factors such as the symmetry, the electronic effects and the characteristics of the terminal functional groups of the ligands have been known to influence 4 strongly the binding affinity and discrimination signal in many examples. [32][33][34] In recent years, a number of thiazole-and styryl-based fluorescent ligands that showed good fluorescence sensing performance towards G-quadruplex nucleic acids have been reported. [35][36][37] .…”

Structural modification of nonspecific thiazole orange for ligand-DNA interaction study: Understanding the ligand recognition selectivity towards G4-DNA over duplex-DNA

“…For the study of ligand-DNA interaction in vitro or in vivo, in order to achieve merit fluorescent signal discrimination and display higher affinity to interact with G4-DNA over duplex-DNA, the design of molecular scaffolds that are able to match with the G4-DNA binding pocket (G-quartet) is crucial. Some recent reports revealed that the feature of a binding ligand such as molecular shape [42], symmetry [43,44], the planarity and polarity of ligands [12,45,46] and the electronic effect of terminal groups [47][48][49], may have significant influence in the ligand-G4-DNA interaction specificity and affinity. In the present study, three new G4-DNA binding ligands based on a relatively rigid thiazole orange (TO) scaffold were synthesized by varying the molecular size and flexibility of the terminal substituent groups for probing the interaction characteristics of the G-quartet of telomeric G4-DNA because the understanding of binding site matching in rational drug design is essential.…”