Amino‐Acid‐Anthraquinone Click Chemistry Conjugates Selectively Target Human Telomeric G‐Quadruplexes

Abstract

Guanine‐rich sequences are known to fold into G‐quadruplex (G4) arrangements, which are present in oncogenes and in the telomeric regions of chromosomes. In particular, G4s represent an obstacle to functioning of telomerase, an enzyme overexpressed in cancer cells causing their immortalization. Therefore, G4 stabilization using small molecules represents an appealing strategy for the medicinal chemist. Ligands based on an anthraquinone scaffold, to which peptidic side chains were attached by an amide bond, were previously reported. We envisioned improving this ligand concept leveraging the click chemistry approach, which, besides representing a flexible, high yielding synthetic strategy, allows an elongation of the side chains and an increase of π–π stacking and H‐bond interactions with the nucleobases through the triazole ring. Compounds were tested for their ability to interact with G4 DNA with a multiple analytical approach, demonstrating an elevated aptitude to stabilize the G4 and high selectivity over double stranded DNA.

Preferential Binding of a Red Emissive Julolidine Derivative to a Promoter G‐Quadruplex

“…[10] The therapeutic potential of G-quadruplexes was noticed nearly three decades ago and subsequent findings of its role in functional regions of the human genome led to several research endeavors towards the development of small molecules for both drug development [11,12] and diagnostic purposes with implications in live cell imaging. [13,14] A wide variety of compounds have been reported to bind to G-quadruplexes [15][16][17][18][19][20][21][22][23] of different molecularities and conformations. Among these molecules, several planar compounds with extended π-systems and capability towards base stacking interactions have demonstrated preferential binding to Gquadruplexes.…”

“…A wide variety of compounds have been reported to bind to G‐quadruplexes [15–23] of different molecularities and conformations. Among these molecules, several planar compounds with extended π‐systems and capability towards base stacking interactions have demonstrated preferential binding to G‐quadruplexes [24,25] .…”