Synthesis, Binding Properties, and Differences in Cell Uptake of G‐Quadruplex Ligands Based on Carbohydrate Naphthalene Diimide Conjugates

Abstract

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Trifunctionalized Naphthalene Diimides and Dimeric Analogues as G-Quadruplex-Targeting Anticancer Agents Selected by Affinity Chromatography

“…In the search for G4-selective ligands as novel anticancer drugs, naphthalene diimides (NDIs) emerged as promising compounds for their ability to interact with G-tetrads. Among the many advantages of NDIs, the most noteworthy are their chemical accessibility and possibility to easily functionalize their aromatic cores with multiple diverse pendant groups, thus allowing a fine modulation of their properties, and particularly of their affinity toward different secondary structure-forming oligonucleotides [7][8][9][10]. For these peculiar features, NDIs have been extensively studied both as fluorescent probes and oligonucleotide-targeting ligands [11,12].…”

“…Indeed, it has been shown that the substitution pattern of their core, as well as the chemical nature of their substituents, plays a crucial role in NDI G4 binding, as well as in G4 vs. duplex DNA selective recognition [8,13]. In this context, some of us recently synthesized a set of NDIs derivatized with alkylamine substituents on the naphthalene core [14,15].…”

Binding and Beyond: What Else Can G‐Quadruplex Ligands Do?

“…This provides many potential opportunities to exploit G4 for the development of new therapeutic strategies. Indeed, our own research groups and many others have reported work driven towards the identification of new G4 ligands as the basis of anticancer, and antiparasitic, therapies. The vast majority of G4 ligands employ rigid aromatic heterocyclic frameworks that are designed to π‐stack onto the large surface of the G‐tetrads .…”

Cyclic Naphthalene Diimide Dimer with a Strengthened Ability to Stabilize Dimeric G‐Quadruplex

“…[10] It also has been proved that G-quadruplex structures formed in G-rich telomeric DNA can inhibitt elomerase activity. [27,28] Our group has been workingo nd esigning novel G4 ligands with improveds pecificity for recognizingG -quadruplex, [29][30][31] and previously we reported cyclic naphthalene diimidec oupling with cyclohexane( cNDI-ch),w hich exhibited as ignificantly highera ffinity( 260-fold) towards binding with G-quadruplex than double-stranded DNA. [14] In addition, some reports already suggested that the G-quadruplex structure in the telomeric sequence assembled like beads on as tring, [15,16] G4 ligands which can selectively target multiple G4 repeats might be promisingf or furthere nhanced specificity on inhibiting telomerase function, and are attractingmore attentionf rom Gquadruplex researchers.…”

“…Over the past several years, some ligandd imers [17][18][19][20][21][22][23][24] and tetramers [25] have been reported with a stronga bility to recognize dimerico rm ultiple G-quadruplex structures,w hich is supportedb yt he fact that the G4 ligand multimer might be ag ood model for stabilizing G-quadruplex repeats.As one important G4 ligand, naphthalene diimide can recognize the G-quadruplex structure through p-p stacking, [26] and its binding affinity to G-quadruplexw as rarely affected even underi nv ivo mimic molecular crowding conditionsa nd may represent superior telomerasei nhibitors in cell nuclei. [27,28] Our group has been workingo nd esigning novel G4 ligands with improveds pecificity for recognizingG -quadruplex, [29][30][31] and previously we reported cyclic naphthalene diimidec oupling with cyclohexane( cNDI-ch),w hich exhibited as ignificantly highera ffinity( 260-fold) towards binding with G-quadruplex than double-stranded DNA. [29] In addition, Chiara Marchetti et al also reported similar macrocyclic naphthalened iimides coupling with the phenylring, which exhibited ah igh selectivity for the G-quadruplex structure and showeda ntiproliferative effectso nc ancerl ines with al ow range of concentrations.…”