Abstract
Non-macrocyclic heteroaryls represent a valuable class of ligands for nucleic acid recognition. In this regard, non-macrocyclic pyridyl polyoxazoles and polyoxadiazoles were recently identified as selective G-quadruplex stabilizing compounds with high cytotoxicity and promising anticancer activity. Herein, we describe the synthesis of a new family of heteroaryls containing oxadiazole and pyridine moieties targeting DNA G-quadruplexes. To perform a structure–activity analysis identifying determinants of activity and selectivity, we followed a convergent synthetic pathway to modulate the nature and number of the heterocycles (1,3-oxazole vs. 1,2,4-oxadiazole and pyridine vs. benzene). Each ligand was evaluated towards secondary nucleic acid structures, which have been chosen as a prototype to mimic cancer-associated G-quadruplex structures (e.g., the human telomeric sequence, c-myc and c-kit promoters). Interestingly, heptapyridyl-oxadiazole compounds showed preferential binding towards the telomeric sequence (22AG) in competitive conditions vs. duplex DNA. In addition, G4-FID assays suggest a different binding mode from the classical stacking on the external G-quartet. Additionally, CD titrations in the presence of the two most promising compounds for affinity, TOxAzaPy and TOxAzaPhen, display a structural transition of 22AG in K-rich buffer. This investigation suggests that the pyridyl-oxadiazole motif is a promising recognition element for G-quadruplexes, combining seven heteroaryls in a single binding unit.
Highlights
G-quadruplex DNAs (G4s) are tetra-helical structures arising in nucleic acid sequences containing repeats of three or four adjacent guanines, self-assembling into square co-planar arrays (G-tetrads), through Hoogsteen hydrogen bonding [1]
2), performing in a of the nature of the aromatic rings composing the ligand on G4 binding, we introduced different single step the synthesis of both oxadiazoles (Pathway A, Scheme 1)
A new series of non-macrocyclic olygoheteroaryls (1–7) containing 1,2,4-oxadiazoles and carboor hero-aromatics were synthesized according to a one-pot, two-step synthesis or following a more time consuming, but more efficient stepwise protocol
Summary
G-quadruplex DNAs (G4s) are tetra-helical structures arising in nucleic acid sequences containing repeats of three or four adjacent guanines, self-assembling into square co-planar arrays (G-tetrads), through Hoogsteen hydrogen bonding [1]. Several G-tetrads, upon K+ coordination [2,3] can stack on each other to form a G4, with the interconnecting sequences extruded as single-strand loops of various length [4,5]. It is well documented that these structures exist in a conformational equilibrium with the single stranded DNA domains transiently generated during key biological processes, such as telomere maintenance, recombination, replication, transcription and epigenetic regulation [6], together with genome instability [7,8]. G4s are considered druggable targets that offer the possibility to control these fundamental processes in cells [9]. Organic compounds capable of recognizing and stabilizing G4 structures have attracted great
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