Search Results (4)

Considering that Cu(tda) chelate (tda: dithioacetate) is a receptor for adenine and related 6-aminopurines, this study reports on the synthesis, molecular and crystal structures, thermal stability, spectral properties and DFT calculations related to [Cu(tda)(9heade)(H₂O)]·2H₂O (1) [9heade: N9-(2-hydroxyethyl)adenine]. Concerning the molecular recognition of (metal chelate)-(adenine synthetic nucleoside), 1 represents an unprecedented metal binding pattern (MBP) for 9heade. However, unprecedentedly, the Cu(tda)-9heade molecular recognition in 1 is essentially featured in the Cu-N1(9heade) bond, without any N6-H⋯O(carboxyl tda) interligand interaction. Nevertheless, N1 being the most basic donor for N9-substituted adenines, this Cu-N1 bond is now assisted by an O2–water-mediated interaction (N6-H⋯O2 and O2⋯Cu weak contact). Also, in the crystal packing, the O-H(ol) of 9heade interacts with its own adenine moiety as a result of an O3–water-mediated interaction (O(ol)-H⋯O3 plus O3-H36⋯π(adenine moiety)). Both water-mediated interactions seem to be responsible for serious alterations in the physical properties of crystalline or grounded samples. Density functional theory calculations were used to evaluate the interactions energetically. Moreover, the quantum theory of atoms-in-molecules (QTAIM), in combination with the noncovalent interaction plot (NCIPlot), was used to analyze the interactions and rationalize the existence and relative importance of hydrogen bonding, chalcogen bonding and π-stacking interactions. The novelty of this work resides in the discovery of a novel binding mode for N9-(2-hydroxyethyl)adenine. Moreover, the investigation of the important role of water in the solid state of 1 is also relevant, along with the chalcogen bonding interactions demonstrated by the density functional theory (DFT) study. Full article

In the last two years, nucleosides analogues, a class of well-established bioactive compounds, have been the subject of renewed interest from the scientific community thanks to their antiviral activity. The COVID-19 global pandemic, indeed, spread light on the antiviral drug Remdesivir, an adenine C-nucleoside analogue. This new attention of the medical community on Remdesivir prompts the medicinal chemists to investigate once again C-nucleosides. One of the essential building blocks to synthetize these compounds is the D-(+)-ribono-1,4-lactone, but some mechanistic aspects linked to the use of different carbohydrate protecting groups remain unclear. Here, we present our investigations on the use of benzylidene as a ribonolactone protecting group useful in the synthesis of C-purine nucleosides analogues. A detailed 1D and 2D NMR structural study of the obtained compounds under different reaction conditions is presented. In addition, a molecular modeling study at the B3LYP/6-31G* level of theory with the SM8 solvation model for CHCl₃ and DMSO to support the obtained results is used. This study allows for clarifying mechanistic aspects as the side reactions and structural rearrangements liked to the use of the benzylidene protecting group. Full article

In the extensive field of metal ions, their interactions with nucleic acids, and their constituents, the main aim of this work is to develop a metal chelate suitable to recognize two molecules of an adenine nucleoside. For this purpose, the dinuclear chelate Cu₂ (µ-EDTA) (ethylenediaminetetraacetate(4-) ion (EDTA)) is chosen as a bicephalic receptor model for N9-(2-hydroxyethyl)adenine (9heade). A one-pot synthesis is reported to obtain the compound [Cu₂(µ₂-EDTA)(9heade)₂(H₂O)₄]·3H₂O, which has been characterized by single-crystal X-ray diffraction and various spectral, thermal, and magnetic methods. The complex unit is a centro-symmetric molecule, where each Cu (II) center is chelated by a half-EDTA, and is further surrounded by an N7-dentate 9heade nucleoside and two non-equivalent trans-O-aqua molecules. The metal chelate-nucleoside molecular recognition is referred to as an efficient cooperation between the Cu-N7(9heade) coordination bond and a (9heade)N6-H···O(carboxyl, EDTA) interligand interaction. Theoretical calculations are also made to account for the relevance of this interaction. The extreme weakness with which each water molecule binds to the metal center disturbs the thermal stability and the infrared (FT-IR) and electron spin resonance (ESR) spectra of the compound. Full article

Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N¹-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N⁹-position, we obtained the N³-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N⁷-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these “base-flipped” analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N³-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N¹ and the N⁶-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis. Full article