Combining Cyclic Triimidazo Triazine Core With Ethynyl‐ N ‐Methyl‐Pyridinium Groups for Targeting G‐Quadruplex Structures

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Abstract
The synthesis and characterization of a mini‐library of cyclic triimidazo triazine ( TT ) derivatives functionalized with one, two, or three ethynyl‐ N ‐methyl‐pyridinium moieties are reported here. These compounds were designed with the aim of targeting cancer‐related DNA G‐quadruplex structures. The newly synthesized compounds were tested for their ability to bind G‐quadruplexes from both telomeric and oncogene promoter sequences using an affinity chromatography‐based assay, spectroscopic and electrophoretic techniques, as well as molecular docking analysis. The obtained results demonstrated the effective capacity of the investigated compounds to specifically recognize the selected G‐quadruplex models, with their TT cores targeting the outer G‐quartets and their positively charged N ‐methyl‐pyridinium groups interacting with the top edge of G‐quadruplex grooves. Notably, the trisubstituted cyclic triimidazole compounds showed higher stabilizing properties than the related disubstituted derivatives, which in turn were stronger binders than their monosubstituted analogs. However, the mono‐ and disubstituted derivatives showed higher G‐quadruplex versus duplex recognition selectivity compared with the trisubstituted ones. Altogether, the biophysical experiments, also in agreement with the biological assays, underlined the advantage of introducing an alkyne linker between the triimidazole core and the methylpyridinium group, proving to be beneficial to increase both the stabilizing effects on the G‐quadruplexes and the anticancer activity compared with the analogs of the same family lacking the alkyne linker.

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