1604841-66-8

Upstream product

• 112-16-3 n-dodecanoyl chloride 
• 623-05-2 (4-hydroxyphenyl)methanol 

Downstream Products

• 1604841-26-0 bis(4-dodecanoyloxybenzyl)-N,N-diisopropylphosphoramidite 

Relevant academic research and scientific papers

Synthesis and Antiviral Evaluation of TriPPPro-AbacavirTP, TriPPPro-CarbovirTP, and Their 1′,2′-cis-Disubstituted Analogues

Herein we describe the synthesis of lipophilic triphosphate prodrugs of abacavir, carbovir, and their 1′,2′-cis-substituted carbocyclic analogues. The 1′,2′-cis-carbocyclic nucleosides were prepared by starting from enantiomerically pure (1R,2S)-2-((benzyloxy)methyl)cyclopent-3-en-1-ol by a microwave-assisted Mitsunobu-type reaction with 2-amino-6-chloropurine. All four nucleoside analogues were prepared from their 2-amino-6-chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro approach) by application of the H-phosphonate route. The TriPPPro compounds were hydrolyzed in different media, in which the formation of nucleoside triphosphates was proven. While the TriPPPro compounds of abacavir and carbovir showed increased antiviral activity over their parent nucleoside, the TriPPPro compounds of the 1′,2′-cis-substituted analogues as well as their parent nucleosides proved to be inactive against HIV.

The DiPPro approach: Synthesis, hydrolysis, and antiviral activity of lipophilic d4T diphosphate prodrugs

Bioreversible protection of the β-phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure-activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids of various lengths and d4T as a model nucleoside. For synthesis of the lipophilically modified diphosphate group, preformed phosphoramidites were allowed to react with nucleotides, and the β-PIII moiety was subsequently oxidized. The chemical and enzymatic stability of these prodrugs was studied in different media such as phosphate buffer (pH 7.3) or CEM cell extracts. In all media, the hydrolysis rate was clearly dependent on the acyl moiety and decreased with increasing alkyl chain length. The compounds showed a markedly lower half-life in cell extracts than in pH 7.3 phosphate buffer due to the presence of enzyme-catalyzed cleavage. In all media, the DiPPro compounds released d4T diphosphate (d4TDP) as the main product beside d4TMP. In antiviral assays, the compounds proved to be at least as potent as d4T against HIV-1 and 2 in wild-type CEM/0 cells. As a proof of concept, compounds with longer acyl residues showed very good anti-HIV activities in thymidine-kinase-deficient cells (CEM/TK-), indicating their ability to penetrate cell membranes and the delivery of phosphorylated metabolites. NDPs delivered! A structure-activity relationship of bioreversibly protected DiPPro-d4TDP was performed. The stability of the compounds was studied in various media such as cell extracts. Stability increased with increasing lipophilicity of the acyl chain. D4TDP was released as main product. Compounds with long acyl residues showed good anti-HIV activities in TK-deficient cells, proving intracellular uptake of the compounds.