Crystal and Molecular Structure of (+)-Carba-Thymidine, C₁₁H₁₀N₂O₆

The Nucleoside Analogue D-carba T Blocks HIV-1 Reverse Transcription

“…This causes a change in conformation of the pseudosugar ring compared to the conformation of the deoxyribose ring of normal nucleosides, which are primarily in either a 3′- endo (North) or 2′- endo (South) conformation 4. Carbocyclic nucleosides tend to adopt an atypical 1′- exo conformation that is principally governed by the steric bulk of the nucleobase, which prefers an equatorial orientation 6. Kinases, in general, prefer nucleosides that are in the South conformation 2, 3, 5.…”

“…The crystal structure of D-carba T shows that it has a P value of 118.6°, suggesting that the position of the 3′-OH is, in some sense, a compromise between the orientations of the locked North and South nucleosides. Because the structure of the pseudosugar of D-carba T is intermediate between the North and South conformations, it might be an acceptable substrate for both kinases and polymerases 6. In addition, the cyclopentane ring is flexible, which might allow for minor adjustments in the conformation of D-carba T that could allow it to satisfy the structural requirements of both kinases and polymerases.…”

The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

“…As mentioned previously, these interactions typically influence the sugars into either a North or South conformation, or more commonly, an equilibrium of the two (Marquez, 1996; Marquez et al, 1996). The loss of these interactions in the carbocyclic analogues resulted in a 1′-exo sugar confirmation, which differs greatly from the standard 2′-exo/3′-endo (North) or 2′-endo/3′-exo (South) conformations, and thus could explain the decreased activity seen with the carbocyclic derivatives (Marquez, 1996; Marquez et al, 1996; Boyer et al, 2009; Kálmán et al, 1989). Recent studies, however, have shown that alterations such as truncation of the CH 2 OH group or addition of an endocyclic double bond to the carbocyclic scaffold (such as that found in Entecavir) could increase the interaction between the 2′ and/or 3′- hydroxyl groups and the nucleoside pharmacophore, thus potentially increasing their biological activity (Marquez, 1996; Marquez et al, 1996).…”

Bicyclic nucleosides and conformational restriction of oligonucleotides

“…NH 3 ; v) CF 3 COOEt, Et 3 N, vi) thymine, N,O-bis(trimethylsilyl)acetamide, TMS-triflate, MeCN; vii) conc. NH 3 , MeOH; viii) Ac 2 O, pyridine, 0 ЊC; ix) TBAF, MeCN, AcOH (28) or Et 3 NؒHF, pyridine (29). T = thymin-1-yl.…”

“…Therefore, the predominant conformations of the cyclopentane-based nucleosides are different from those of the natural nucleosides. 29 In order to restrict the conformation of cyclopentane-based nucleotide monomers for modified oligonucleotides, two different methano-linked analogues have been synthesised.…”