Synthesis of Novel Nucleoside Analogues Built on a Bicyclo[4.1.0]heptane Scaffold

Abstract

A new class of carbocyclic nucleoside analogues built on a bicyclo[4.1.0]heptane scaffold, a perspective novel pseudosugar pattern, have been conceived as anti-HSV agents on the basis of initial protein-ligand docking studies. The asymmetric synthesis of a series of these compounds incorporating different nucleobases has been efficiently completed starting from 1,4-cyclohexanedione.

Enantiocontrolled Preparation of ϒ-Substituted Cyclohexenones: Synthesis and Kinase Activity Assays of Cyclopropyl-Fused Cyclohexane Nucleosides

“…Thus, the affinity of the synthesized compounds 2a – e for the cellular and HSV-1 thymidine kinases (TKs) were investigated ( Table 2 ). Based on these results, it can be concluded that compounds 2b and, to a lesser extent, 2d , were nicely recognized by herpes simplex virus-TK (IC 50 = 1.6 ± 0.1 µg/mL and 52 ± 28 µg/mL, respectively), in agreement with our modelling studies [ 14 ]. Only compound 2b showed some marginal affinity for mitochondrial TK-2, in addition to its excellent affinity for HSV-1 TK.…”

“…Next, we turned our attention to the use of chiral cyclohexanol R -( 6 ) as the starting material in the preparation of the cytosine analogue 2e, following an adaptation of our earlier work [ 14 ]. Accordingly, the synthesis of 2e ( Scheme 2 ) started with the cyclopropanation reaction on ( R )- 6 , which was first attempted using Shi’s carbenoid (CF3COOZn CH2I) [ 29 , 30 ].…”

“…In a previous work, we reported the synthesis of the nucleoside analogues (NAs) 2a – d built on a bicyclo [4.1.0]heptane scaffold, starting from cyclohexenone 3 bearing a dihydrobenzoin moiety as the chiral auxiliary [ 14 ]. These NAs were designed as potential antiherpetic agents by a molecular modeling study on the HSV-1 TK active site that is involved in the first phosphorylation step of the activation process.…”

Conformationally Locked Carbocyclic Nucleosides Built on a 4′-Hydroxymethyl-3′-hydroxybicyclo[4.1.0]heptane Template. Stereoselective Synthesis and Antiviral Activity

“…Over the past years, our research group has worked on the development of new routes for the enantioselective preparation of cyclohexane NAs as prodrug candidates . We recently described the design and synthesis of a new class of CNAs based on a bicyclo[4.1.0]­heptane scaffold . As part of our continuing research program to identify bioactive NAs, we were interested in developing novel cyclohexenyl-G derivatives bearing an appended cyclopropyl ring 1a , b and unnatural bases, such as a triazole heterocycle 3a – e (Figure ).…”

“… 25 We recently described the design and synthesis of a new class of CNAs based on a bicyclo[4.1.0]heptane scaffold. 26 As part of our continuing research program to identify bioactive NAs, we were interested in developing novel cyclohexenyl-G derivatives bearing an appended cyclopropyl ring 1a , b and unnatural bases, such as a triazole heterocycle 3a – e ( Figure 1 ). It was expected that the fusion to a cyclopropane would impart a significant rigidity to the resulting nucleosides similar to that of the cyclohexene moiety but should be less prone to hydrolytic processes and have more lipophilicity.…”