cycloSal-Pronucleotides of 2‘-Fluoro-ara- and 2‘-Fluoro-ribo-2‘,3‘- dideoxyadenosine as a Strategy to Bypass a Metabolic Blockade

Abstract

Novel, lipophilic cycloSal triesters 4a-c and 5a-c were synthesized, respectively, from the ara- and ribo-configurated 2'-fluorinated-2', 3'-dideoxyadenosines 2 and 3. The cycloSal phosphotriesters were used as tools to study the effects of the two different sugar pucker conformations induced by two opposite configurations of the fluorine substituent at C2' of the dideoxyribose moiety. F-ara-ddA (2) is known to be an active anti-HIV agent, whereas the ribo-analogue 3 is inactive. Hydrolysis studies with the triester precursors 4a-c and 5a-c showed selective formation of the monophosphates of 2 and 3. The lipophilicity of the triester prodrugs was considerably increased by the cycloSal mask with respect to ddA (1), F-ara-ddA (2), and F-ribo-ddA (3). Phosphotriesters 4 and 5 proved to be completely resistant to ADA and AMPDA deamination. In parallel experiments, ribo-nucleoside 3 showed a 50-fold faster deamination rate relative to the ara-analogue 2. Against HIV in CEM cells, the phosphotriesters 4 proved to be 10-fold more potent than the parent nucleoside 2. Furthermore, the prodrugs 4 were active against MSV-induced transformation of C3H/3T3 fibroblasts, while 2 was inactive. More interestingly, the ribo-configurated phosphotriesters 5, prepared from the inactive F-ribo-ddA (3), showed a level of anti-HIV activity that was even higher than that of F-ara-ddA (2). Our findings clearly prove that the application of the cycloSal-pronucleotide concept to F-ribo-ddA (3) overcomes a metabolic blockade in the formation of the corresponding monophosphate.

Linear Synthesis of Chiral cycloSal‐Pronucleotides

“…The methanolysis was carried out according to a literature procedure. [16] The enantiomeric ratio was determined by means of HPLC on a chiral stationary phase. The result was then compared with those obtained with racemic Salithion (31).…”

“…Moreover, only one isomer was found to be a strong inhibitor of the enzyme butyrylcholinesterase. [15] Although in previous studies a few cycloSal-triesters were separated by (time-consuming) semipreparative HPLC, [14,16] it is clearly advantageous to synthesize these compounds stereoselectively. Recently, we described a first convergent, stereospecific preparation of isomerically pure cycloSal-pronucleotides based on chiral N-cyaniminooxazolidines.…”

Fluorinated Nucleosides as an Important Class of Anticancer and Antiviral Agents

“…F-ara-ddA is an active anti-HIV agent, whereas the ribo-analogue is inactive. Interestingly, the ribo-configured phosphotriesters prepared from the inactive F-ribo-ddA showed a level of anti-HIV activity that was even higher than that of F-ara-ddA [5]. Therefore stability and potential therapeutic activity of both conformations vary according to different substitutions on the nucleosides [6].…”

Synthesis and conformational behavior of the difluoromethylene linked C-glycoside analog of β-galactopyranosyl-(1↔1)-α-mannopyranoside

“…6 Second, based on the unusual conformational properties of 2-fluoroethanols and related structures, such fluoro-C-glycosides are expected to have a more well defined conformational bias than the exact C-glycoside with respect to the intersaccharide linker, such that they may more closely mimic the conformational properties of the O-glycoside. 7,8 Indeed, the use of CHF and CF 2 as isosteres of oxygen has been examined in other molecules of biological interest, and examples of CF 2 linked C-furanosides have been prepared. 9,10, 11 We have previously reported the synthesis and conformational behavior of 2, 3 and 4 ,12,13 the exact and the CHF linked analogues of 1, a known O-disaccharide mimetic of sialyl Lewis X ( Figure 1).…”