Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication

Abstract

In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2'-C-methyl containing nucleosides, 2'-C-Me-cytidine, 2'-C-Me-uridine and 2'-C-Me-2'-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5'-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ∼550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.

Biocatalytic Enantioselective Hydroaminations for Production of N‐Cycloalkyl‐Substituted L‐Aspartic Acids Using Two C−N Lyases

“…N ‐substituted L‐aspartic acids are noncanonical amino acids that have wide applications in pharma‐ and nutraceutical fields, serving as drug candidates and chiral building blocks for pharmaceutically active molecules, artificial sweeteners and peptido‐mimetics . Therefore, the development of methodologies for the efficient synthesis of N ‐substituted aspartic acids in enantioenriched form is of high academic and industrial interest.…”

“…N-substituted L-aspartic acids are noncanonical amino acids that have wide applications in pharma-and nutraceutical fields, serving as drug candidates and chiral building blocks for pharmaceutically active molecules, artificial sweeteners and peptidomimetics. [1][2][3][4][5][6][7] Therefore, the development of methodologies for the efficient synthesis of N-substituted aspartic acids in enantioenriched form is of high academic and industrial interest. The most common chemocatalytic synthetic strategy is the Michael addition of suitable amines to maleic acid, fumaric acid, their ester or amide derivatives, or monoalkali salts.…”

Bifunctional aryloxyphosphoramidate prodrugs of 2′-C-Me-uridine: synthesis and anti-HCV activity

“…Coupling with 2′- C -methyl-2′,3′- O -isopropylidene-uridine, which was prepared according to a literature protocol, 12 furnished the 2’- C -Me-2′,3′- O -isopropylidene-uridine ProTide analogues 30a-k . Finally, acidic deprotection afforded the desired target compounds 31a-k .…”

“…The choice of the isoamyl ester moiety is dictated by the fact that these ester groups were found to be optimal to confer antiviral activity to L-aspartic acid based aryloxyphosphoramidate nucleoside prodrugs. 12 …”

“…In some cases, compounds exhibited improved activity relative to the corresponding L-alanine derived ProTides, depending on the ester moiety of the two carboxylic acid moieties of L-aspartic acid. 12 Given these promising data, we have explored other bifunctional amino acids (L-glutamic acid, L-serine, L-threonine and L-tyrosine) as potential alternatives for L-alanine, using 2’- C -Me-uridine as prototype nucleoside. As in previous reports on ProTides, the L-stereochemistry was found to be superior when compared to the D-enantiomers, we focused on the synthesis of ProTides with amino acids having the natural L-stereochemistry.…”