Synthesis, Antiviral Evaluation, and Computational Studies of Cyclobutane and Cyclobutene L‐Nucleoside Analogues

Abstract

This paper describes the stereoselective synthesis of a series of functionalized cyclobutane and cyclobutene L‐nucleoside analogues featuring a methylene spacer between the carbocycle and the nucleobase. These L‐nucleoside analogues were subjected to comprehensive screening for antiviral activity. To obtain knowledge at the molecular structural level relevant for designing future analogues, the mechanism of action of these L‐nucleoside analogues as anti‐herpes simplex virus agents was investigated by computational approaches. In particular, protein–ligand docking calculations were used to rationalize the ability of the prodrug candidates to be activated. Docking experiments were performed on the three kinases involved in the activation process of thymine and guanine derivatives.

Recent Advances in the Synthesis of Cyclobutanes by Olefin [2 + 2] Photocycloaddition Reactions

“… 532 − 539 Significant diastereoselectivities were recorded in several intermolecular [2 + 2] photocycloaddition reactions, and numerous applications were disclosed for the enantioselective synthesis of terpenoid natural products 540 − 545 and new nucleoside analogues ( Scheme 96 ). 546 − 549 …”

Nucleobase coupling by Mitsunobu reaction towards nucleoside analogs

“…Scheme 13. Coupling of guanine precursors to two different carbasugars has been reported by Miralles-Llumà et al66 …”

“…Guanine nucleoside analogs are frequently prepared by coupling 2-amino-6-chloropurine and derivatives, namely 2-acetamido-6-chloropurine, 44 2-(tert-butoxycarbonyl)amino-6-chloropurine 33 and 2-[bis(tertbutoxycarbonyl))amino]-6-chloropurine, followed by acid 66 or basic treatment. 67 Mohamed et al 65 achieved the coupling of 2-amino-6-chloropurine to a carbocyclic vinylphosphonate by MR to give the corresponding nucleoside analog in 80% yield, which was transformed in the carbocyclic vinylphosphonate derivative of guanine.…”

“…67 Mohamed et al 65 achieved the coupling of 2-amino-6-chloropurine to a carbocyclic vinylphosphonate by MR to give the corresponding nucleoside analog in 80% yield, which was transformed in the carbocyclic vinylphosphonate derivative of guanine. Also, Miralles-Llumà et al 66 took advantage of MR to couple this nucleobase to a cyclobutyl unit obtaining 47 in 87% yield. However the same nucleobase failed to couple with the alcohol 48, but with the 2-[bis(tert-butoxycarbonyl)amino]-6-chloropurine, MR coupling generated the nucleoside analog 50 in 60% yield (Scheme 13).…”

Advances in Therapeutic L-Nucleosides and L-Nucleic Acids with Unusual Handedness

“…Above, we listed some of the L -nucleoside analogues with a solid demonstration of their therapeutic activities, which are summarized in Table 1 . Besides, there are many other nucleoside-like small molecules designed and evaluated as antiviral therapeutics, which had an L -configuration similar to its modified nucleoside, including cyclobutene L -nucleoside analogues [ 72 ], L -erythro-hexopyranosyl nucleosides [ 73 , 74 ], L -4′-C-ethynyl-2′-deoxypurine nucleosides [ 75 ], L -ribo-configured Locked Nucleic Acid [ 76 , 77 , 78 , 79 ], pyrrolo, pyrazolo, or imidazo-modified L -nucleoside [ 80 ], et al There have also been many methods developed to efficiently synthesize carbocyclic L -nucleoside analogues [ 52 , 81 , 82 , 83 ], and they have been summarized elsewhere [ 84 , 85 ].…”