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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Michielssens, Servaas Maiti, Mohitosh Herdewijn, Piet Lescrinier, Eveline Ceulemans, Arnout Maiti, Munmun Dyubankova, Natalia |
| Description | Author Affiliation: Maiti M ( Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.) |
| Abstract | Nucleoside phosphoramidates (NPs) are a class of nucleotide analogues that has been developed as potential antiviral/antitumor prodrugs. Recently, we have shown that some amino acid nucleoside phosphoramidates (aaNPs) can act as substrates for viral polymerases like HIV-1 RT. Herein, we report the synthesis and hydrolysis of a series of new aaNPs, containing either natural or modified nucleobases to define the basis for their differential reactivity. Aqueous stability, kinetics, and hydrolysis pathways were studied by NMR spectroscopy at different solution pD values (5–7) and temperatures. It was observed that the kinetics and mechanism (PN and/or PO bond cleavage) of the hydrolysis reaction largely depend on the nature of the nucleobase and amino acid moieties. Aspartyl NPs were found to be more reactive than Gly or β-Ala NPs. For aspartyl NPs, the order of reactivity of the nucleobase was 1-deazaadenine>7-deazaadenine>adenine>thymine≥3-deazaadenine. Notably, neutral aqueous solutions of Asp-1-deaza-dAMP degraded spontaneously even at 4 °C through exclusive PO bond hydrolysis (a 50-fold reactivity difference for Asp-1-deaza-dAMP vs. Asp-3-deaza-dAMP at pD 5 and 70 °C). Conformational studies by NMR spectroscopy and molecular modeling suggest the involvement of the protonated N3 atom in adenine and 1- and 7-deazaadenine in the intramolecular catalysis of the hydrolysis reaction through the rare syn conformation. |
| ISSN | 09476539 |
| e-ISSN | 15213765 |
| Journal | Chemistry - A European Journal |
| Issue Number | 3 |
| Volume Number | 18 |
| Language | English |
| Publisher | Wiley-VCH;ChemPubSoc Europe |
| Publisher Date | 2012-01-16 |
| Publisher Place | Germany |
| Access Restriction | Open |
| Subject Keyword | Amides Chemistry Antiviral Agents Chemical Synthesis Nucleosides Phosphoric Acids Prodrugs Adenine Analogs & Derivatives Amino Acids Crystallography, X-Ray HIV-1 Drug Effects Kinetics Magnetic Resonance Spectroscopy Models, Theoretical Molecular Conformation Structure-Activity Relationship Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Organic Chemistry Catalysis |
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