Synthesis and Characterization of Bis-Triazolyl-Pyridine Derivatives as Noncanonical DNA-Interacting Compounds

Abstract

Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells.

Cyclic Triimidazoles as Stabilizers for Gene Promoter and Human Telomeric DNA G‐Quadruplexes

“…Also, the position of the charge and the flexibility of the chain on which it is located, drastically affect the thermal stabilization properties of a ligand [32] . Here, the highest thermal stabilization effects were observed for the TT derivatives decorated with the guanyl hydrazone groups followed by the p ‐methylpyridinium ones, while the o ‐methylpyridinium substituents caused a drastic drop of the ligand‐induced stabilization properties.…”

2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors

“…The alkyne precursors (23, 25, and 27) were prepared from propargyl bromide and the corresponding amine or amine hydrochloride through S N 2 substitution (Scheme 2). 54 The generated alkyne precursors (23, 25, and 27) were then coupled with 6-bromo-4-methylpyridin-2amine (21, Scheme 1) via Sonogashira cross-coupling [48][49] The synthetic approaches to compounds 15-16 are outlined in Scheme 3. The Sonogashira cross-coupling reaction 51 between 6-bromo-4-methylpyridin-2-amine (21) and but-3-yn-1-ol was carried out at 120 • C under an inert atmosphere to obtain the corresponding alkynyl alcohol in 70% yield.…”

“…Compounds 23, 25, and 27 were prepared following a reported procedure with slight modifications (Scheme 2). 54 To a stirred suspension of 4,4-difluoropiperidine hydrochloride (0.500 mg, 3.170 mmol, 1.0 equiv) and K 2 CO 3 (877 mg, 6.350 mmol, 2.0 equiv) in anhydrous CH 3 CN (10 mL) at 25 • C, a solution of propargyl bromide (0.420 mL, 3.810 mmol, 80% in toluene, 1.2 equiv) in anhydrous CH 3 CN (2 mL) was added. The mixture was allowed to stir at 25 • C for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was diluted with water and then extracted with DCM (3 × 15 mL).…”

Selective Ligands for Non-Canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?

“…Among new ligands, a group of bis-triazolyl pyridines was synthesized and investigated by Di Porzio and colleagues [ 8 ]. The design of these molecules fulfilled three requirements: a planar aromatic system for stacking purposes, a V-shaped form to maximize interactions with G4, and two or three positively charged groups to reinforce binding.…”