The evaluation of 5-amino- and 5-hydroxyuracil derivatives as potential quadruplex-forming agents

Abstract

5-Substituted uracils (NH or OH groups in position 5) have been examined theoretically and experimentally as potential building blocks in quadruplex structures. Our high level Density Functional Theory (DFT) calculations showed that the tetramer formation and stacking energies for 5-substituted uracils are similar to the energies of purine-based xanthine (X) or guanine (G) structures. As tetrads of 5-substituted uracils cover almost exactly the same area as purine tetrads, mixed tetrads or quadruplex structures based on X or G and 5-substituted uracil motifs are possible. According to the calculations, 5-hydroxyuracil-based structures are the best candidates for experimental implementation which was corroborated by the existence of higher complexes in the mass spectra of 1-benzyl-5-hydroxyuracil. These pyrimidine-based molecules can be used as efficient building blocks in different applications including aptamers, bio-sensors or - taking into account the larger cavity in the central region of 5-hydroxyuracil structures - as an artificial ion channel.

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

“…The n 5 dU tetrad was observed having circular double H-bonds and this provided higher stability than T or br 5 U [ 49 ]. Using Density Functional Theory calculations and ESI-MS measurements, Paragi et al [ 50 ] hypothesized that 5-amino- and especially 5-hydroxyuracils can form full pyrimidine and also mixed tetrads with guanine or xanthine, where tetrads have similar energy and cover almost exactly the same area as the full guanine or xanthine tetrads.…”

Human DNA Telomeres in Presence of Oxidative Lesions: The Crucial Role of Electrostatic Interactions on the Stability of Guanine Quadruplexes

“…Tetrads can, in addition, form a π-stacking interaction with other planes, leading to a super structure composed of the superposition of different tetrads, up to three or four units. Interestingly, the specific arrangements dictated by the Hoogsteen hydrogen bonds [37,38,39,40] lead to an accumulation of negative charge close to the center of the plan, hence G4s need to be stabilized by the inclusion of cations, such as K + and Na + , in their central channel [41]. G4s may exist in a delicate equilibrium between different conformers differing for the orientation of the dihedral angles of the backbone, giving rise to parallel, antiparallel, and hybrid arrangements [42].…”

The Crystal Structure of 5‐Aminouracil and the Ambiguity of Alternative Polymorphs

“…With its 5-amino group, AUr was the first pyrimidine derivative shown to recognize all four DNA nucleobases (guanine, adenine, thymine, cytosine), and thereby provide additional stabilization for triple helical [2] and potentially quadruplex DNA assemblies. [3] The biological activity of AUr has also been demonstrated in other contexts [4] as has its use as a reagent in the synthesis of other heterocycles. [5] Despite the significant biological and theoretical interest in this compound, no experimental crystal structure of AUr has yet been reported, in part due to its propensity to deposit as microcrystalline aggregates.…”