Abstract
G-quadruplexes (G4s) are higher-order supramolecular structures, biologically important in the regulation of many key processes. Among all, the recent discoveries relating to RNA-G4s, including their potential involvement as antiviral targets against COVID-19, have triggered the ever-increasing need to develop selective molecules able to interact with parallel G4s. Naphthalene diimides (NDIs) are widely exploited as G4 ligands, being able to induce and strongly stabilize these structures. Sometimes, a reversible NDI-G4 interaction is also associated with an irreversible one, due to the cleavage and/or modification of G4s by functional-NDIs. This is the case of NDI-Cu-DETA, a copper(II) complex able to cleave G4s in the closest proximity to the target binding site. Herein, we present two original Cu(II)-NDI complexes, inspired by NDI-Cu-DETA, differently functionalized with 2-(2-aminoethoxy)ethanol side-chains, to selectively drive redox-catalyzed activity towards parallel G4s. The selective interaction toward parallel G4 topology, controlled by the presence of 2-(2-aminoethoxy)ethanol side chains, was already firmly demonstrated by us using core-extended NDIs. In the present study, the presence of protonable moieties and the copper(II) cavity, increases the binding affinity and specificity of these two NDIs for a telomeric RNA-G4. Once defined the copper coordination relationship and binding constants by competition titrations, ability in G4 stabilization, and ROS-induced cleavage were analyzed. The propensity in the stabilization of parallel topology was highlighted for both of the new compounds HP2Cu and PE2Cu. The results obtained are particularly promising, paving the way for the development of new selective functional ligands for binding and destructuring parallel G4s.
Highlights
Nucleic acid (NA) sequences rich in guanine-basis (Gs) can fold into four-stranded higher-order supramolecular structures known as G-quadruplexes (G4s) [1,2].Over the past decades, G4s have gained increasing attention in medicinal chemistry being mainly clustered in top genomic regions, as telomeres, gene promoters, open reading frames, and untranslated regions, and not randomly distributed across the cell genome [3]
The reaction course was monitored by analytical HPLC, comparing the results with those gained with the previous protocol [17]
We have proposed the design and synthesis of two novel Cu(II)-Naphthalene diimides (NDIs) complexes for the selective cleavage of parallel G4s triggered by reactive oxygen species (ROS)
Summary
G4s have gained increasing attention in medicinal chemistry being mainly clustered in top genomic regions, as telomeres, gene promoters, open reading frames, and untranslated regions, and not randomly distributed across the cell genome [3]. They are recognized as key NA secondary structures involved in the regulation of different biological processes, whose targeting can be exploited as a revolutionary therapeutic approach to tackle a growing list of different pathologies, such as cancer [4], neurodegenerative diseases [5], viral infections [6], not least COVID-19 [7]. Telomeric repeat-containing RNAs folded into G4s (TERRA) are involved in numerous processes, including the regulation of telomerase functioning [10], as well as the regulation of viral activity which can be affected by RNA-G4s folding [11]
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