Impact of the 2′- and 3′-Sugar Hydroxyl Moieties on Gas-Phase Nucleoside Structure

Abstract

Modified nucleosides have been an important target for pharmaceutical development for the treatment of cancer, herpes simplex virus, and the human immunodeficiency virus (HIV). Amongst these nucleoside analogues, those based on 2′,3′-dideoxyribose sugars are quite common, particularly in anti-HIV applications. The gas-phase structures of several protonated 2′,3′-dideoxyribose nucleosides are examined in this work and compared with those of the analogous protonated DNA, RNA, and arabinose nucleosides to elucidate the influence of the 2′-and combined 2′,3′-hydroxyl groups on intrinsic structure. Infrared multiple photon dissociation (IRMPD) action spectra are collected for the protonated 2′,3′-dideoxy forms of adenosine, guanosine, cytidine, thymidine and uridine, [ddAdo+H] + , [ddGuo+H] + , [ddCyd+H] + , [ddThd+H] + , and [ddUrd+H] + , in the IR fingerprint and hydrogen-stretching regions. Molecular mechanics conformational searching followed by electronic structure calculations generates low-energy conformers of the protonated 2′,3′dideoxynucleosides and corresponding predicted linear IR spectra to facilitate interpretation of the measured IRMPD action spectra. These experimental IRMPD spectra and theoretical calculations indicate that the absence of the 2′-and 3′-hydroxyls largely preserves the protonation preferences of the canonical forms. The spectra and calculated structures indicate a slight preference for C3′-endo sugar puckering. The presence of the 3′-and further 2′-hydroxyl increases the available intramolecular hydrogen-bonding opportunities and shifts the sugar puckering modes for all nucleosides but the guanosine analogues to a slight preference for C2′-endo over C3′-endo.

Influence of 5-Halogenation on the Base-Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities of Synthetici-Motif Structures for DNA Nanotechnology Applications

“…The primary and sequential dissociation behavior observed for these ( x Cyd)­H + ( x Cyd) base pairs parallels that observed previously for protonated base pairs of cytosine nucleobase and cytidine nucleoside analogues − ,, and that of isolated protonated cytidine nucleoside analogues − using GIBMS and IRMPD approaches.…”

“…Entropies of activation at 1000 K, Δ S † (PSL), calculated from the molecular constants used for RRKM lifetime modeling are listed in Table . The entropies of activation at 1000 K are large and positive and vary from 82 to 109 J·mol –1 K –1 , consistent with expectations for cleavage of multiple noncovalent interactions in the CID process and occurring via a loose PSL TS. − The extent of kinetic shifting associated with the finite experimental time window is estimated by modeling the CID cross sections without accounting for lifetime effects. Without inclusion of the RRKM formalism in the modeling, the threshold values determined increase by 1.74, 1.72, 1.86, and 1.72 eV for the base pairs of the DNA analogues, x Cyd = fl 5 dCyd, cl 5 dCyd, br 5 dCyd, and io 5 dCyd, and by 1.52, 1.64, 1.61, and 1.97 eV for the base pairs of the RNA analogues, x Cyd = fl 5 Cyd, cl 5 Cyd, br 5 Cyd, and io 5 Cyd, respectively.…”

Influence of 5-Methylation and the 2′- and 3′-Hydroxy Substituents on the Base Pairing Energies of Protonated Cytidine Nucleoside Analogue Base Pairs: Implications for the Stabilities ofi-Motif Structures

“…Two sequential dissociation pathways, both of which involve glycosidic bond cleavage occur in competition. In all cases, the excess proton is preferentially retained by the departing base, reaction , whereas retention of the excess proton by the sugar moiety is much less favorable (by more than an order of magnitude), reaction . The fragmentation patterns observed for the ( x Cyd)­H + ( x Cyd) base pairs parallel those observed in previous studies of protonated base pairs of cytosine nucleobase and cytidine nucleoside analogues as well as that of iosloated protonated cytidine nucleoside analogues using TCID − , and IRMPD − techniques.…”

5-Halogenation of Uridine Suppresses Protonation-Induced Tautomerization and Enhances Glycosidic Bond Stability of Protonated Uridine: Investigations via IRMPD Action Spectroscopy, ER-CID Experiments, and Theoretical Calculations

“…Present results are consistent with previous findings for protonated uridine 24 and a series of sugar-modified uridine nucleoside analogues, ddUrd, dUrd, araUrd, Urdm, and Urdfl, where a diverse mixture of T and O4 conformers are populated. 24,25,27,28 Among these uridine nucleoside analogues, T conformers are favored over O4-protonated conformers for dUrd, Urd, Urdm, and Urdfl, whereas O4-protonated conformers are favored over T conformers for ddUrd and araUrd. In contrast, a diverse mixture of T and O2-protonated conformers are populated for the 5-methylated uridine nucleoside analogues, dThd, Thd, and Thdm.…”

“…Uracil (Ura), the nucleobase of Urd, possesses two keto moieties that may be susceptible to tautomerization depending upon the local environment and thus provides a handle for altering the properties of uridine nucleosides. Tautomerization of uracil occurs readily upon protonation, resulting in the 2,4-dihydroxy tautomer. − Protonation-induced tautomerization has also been observed for several modified uracils including 5-methyluracil (thymine), 5-halouracils, 2-thiouracil, 4-thiouracil, and 2,4-dithiouracil. − Likewise, protonation-induced tautomerization has also been observed for uridine nucleoside analogues including 5-methyluridine (thymidine, Thd), 5-methyl-2′-deoxyurdine (dThd), and several modified at the 2′-position of the ribose moiety including 2′-deoxyuridine (dUrd), 2′,3′-dideoxyuridine (ddUrd), 2′-O-methyluridine (Urdm), 2′-O-methyl-5-methyluridine (dThdm), 2′-fluorouridine (Urdfl), and uracil arabinoside (araUrd). − This unique character of protonated uracil suggests that a variety of conformations may be accessible to protonated uridine, [Urd+H] + , and its analogues. Indeed, combined IRMPD action spectroscopy and computational work has established that a diverse mixture of 2,4-dihydroxy tautomers and either O4- and/or O2-protonated conformers are populated by these uridine nucleoside analogues when generated by electrospray ionization. − …”