Photoactivatable V‐Shaped Bifunctional Quinone Methide Precursors as a New Class of Selective G‐quadruplex Alkylating Agents

Abstract

Combining the selectivity of G‐quadruplex (G4) ligands with the spatial and temporal control of photochemistry is an emerging strategy to elucidate the biological relevance of these structures. In this work, we developed six novel V‐shaped G4 ligands that can, upon irradiation, form stable covalent adducts with G4 structures via the reactive intermediate, quinone methide (QM). We thoroughly investigated the photochemical properties of the ligands and their ability to generate QMs. Subsequently, we analyzed their specificity for various topologies of G4 and discovered a preferential binding towards the human telomeric sequence. Finally, we tested the ligand ability to act as photochemical alkylating agents, identifying the covalent adducts with G4 structures. This work introduces a novel molecular tool in the chemical biology toolkit for G4s.

Structural insights and shedding light on preferential interactions of dietary flavonoids with G-quadruplex DNA structures: A new horizon

“…According to a bioinformatics study, the human genome contains 700,000 potential G-quadruplex producing sequences [ 16 ]. The fascinating fact is that such constructions are not distributed randomly; somewhat more, they are strongly associated with major regulatory areas such as telomeres, replication origins, promoters, 3′-UTR and 5′-UTR, RBS (Ribosome Binding Sites), and long non-coding RNA in which they attenuate expression of genes, implying that G-quadruplex structures may play an important role in the regulation of a wide range of cellular procedures.…”

Targeting the RNA G-Quadruplex and Protein Interactome for Antiviral Therapy

“…Photoactivation can generate ROS to break down RNA G4s and then inhibit KRAS and NRAS expression, eventually inducing apoptosis . Similar new photoactivated alkyl ligands are being continuously studied and designed. , Since G4 structures also widely exist in viruses, it is possible that such PDT may also be applied to antiviral therapy in the future.…”

“…132 Similar new photoactivated alkyl ligands are being continuously studied and designed. 119,133 Since G4 structures also widely exist in viruses, it is possible that such PDT may also be applied to antiviral therapy in the future.…”

Selective Chemical Modification to the Higher‐Order Structures of Nucleic Acids

“…Recently, the bisquinone methides, which have the potential to react to G4 with intrastrand crosslinks, have been reported. [85] G4 alkylating agents have also been developed in which the G4 ligand PDS is attached the photoalkylating group (XL), for example, benzophenone (Bz) or aryl azide (N 3 ) by different linkers (Figure 21). [86] Alkylation of these PDSÀ XL derivatives to the G4 structure was investigated, and the alkylation site to the G4 structure varied depending on the reactive group.…”

“…But bis‐adducts arising from PDS−Chl at both A and G is negligible. Recently, the bisquinone methides, which have the potential to react to G4 with intrastrand crosslinks, have been reported [85] …”