Chemical and Structural Implications of 1‘,2‘- versus 2‘,4‘- Conformational Constraints in the Sugar Moiety of Modified Thymine Nucleosides

Abstract

In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1',2'-azetidine- and 1',2'-oxetane-fused thymidines, as well as their 2',4'-fused thymine (T) counterparts such as LNA-T, 2'-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1',2'-fused or a tricyclic 2',4'-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37 degrees +/- 27 degrees , phi(m) = 25 degrees +/- 18 degrees ) of the 1',2'-fused systems, and (ii) pure North type (P = 19 degrees +/- 8 degrees , phi(m) = 48 degrees +/- 4 degrees ) for the 2',4'-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1',2'- or 2',4'-linked modification. The comparison of pK(a)s of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical and experimental measurements showed that the nature of the sugar conformational constraints steer the physicochemical property (pK(a)) of the constituent 1-thyminyl moiety, which in turn can play a part in tuning the strength of hydrogen bonding in the basepairing.

SN- and NS-puckered sugar conformers are precursors of the (6–4) photoproduct in thymine dinucleotide

“…Such results are fully in line with NMR/theoretical calculations and X-ray crystallographic analysis performed on the N-locked nucleoside 6 , free 28,29 or incorporated into oligonucleotides. 30,31 The large ν max (entries 3, 6 and 7) resulted from the 2′- O ,4′- C -methylene linkage constraint.…”

Polyamine‐Functionalized 2′‐Amino‐LNA in Oligonucleotides: Facile Synthesis of New Monomers and High‐Affinity Binding towards ssDNA and dsDNA

“…The same relation between duplex stabilization and salt concentration was observed for the two reference strands ON1 and ON2 . This was expected, as the p K a value of the 2′‐amino group in 2′‐amino‐LNA‐T has been reported to be 6.17 [46] …”

“…[45] The same relationb etween duplex stabilization and salt concentration was observed for the two reference strands ON1 and ON2.T his was expected, as the pK a value of the 2'-amino group in 2'-amino-LNA-Th as been reported to be 6.17. [46] Binding specificity was assessed for ON3, ON4 and ON5 in comparison with ON1 with the nucleobase complementary to the site of modification on the opposite strandsb eing varied from adenosine to guanine, cytosine or thymine/uracil centrally (Table S3 in the SupportingI nformation). Here X-LNA-T induced ad ecrease in T m of 16.0 8Cw ith respect to guanine in the DNA/DNA duplex,w hile Y-and Z-LNA-T resulted in ad estabilization of 13.5 8C.…”

Acid-base and lipophilic properties of peptide nucleic acid derivatives

“…Notably, the potential of IAM indices to predict passive transport through biological barriers can be of particular relevance in near future to estimate pharmacokinetic properties of compounds with potential pharmacological applications. Overall, to the authors’ best knowledge, no study on the ionization properties and lipophilicity of peptide nucleic acid monomers and oligomers has so far been reported [ 34 ].…”