N(4)-Acyl derivatives as lipophilic prodrugs of cidofovir and its 5-azacytosine analogue, (S)-HPMP-5-azaC: chemistry and antiviral activity
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24731540
DOI
10.1016/j.bmc.2014.03.031
PII: S0968-0896(14)00216-8
Knihovny.cz E-resources
- Keywords
- 5-Azacytosine, Acyclic nucleoside phosphonates, Antivirals, Cidofovir, HPMP-5-azaC, Phosphonate ester, Prodrug,
- MeSH
- Antiviral Agents chemical synthesis chemistry pharmacology MeSH
- Cidofovir MeSH
- Cytosine analogs & derivatives chemical synthesis chemistry pharmacology MeSH
- Herpesviridae drug effects MeSH
- Hydrophobic and Hydrophilic Interactions * MeSH
- Microbial Sensitivity Tests MeSH
- Molecular Structure MeSH
- Organophosphonates chemical synthesis chemistry pharmacology MeSH
- Prodrugs chemical synthesis chemistry pharmacology MeSH
- Virus Replication drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antiviral Agents MeSH
- Cidofovir MeSH
- Cytosine MeSH
- N-(5-((2-(2-(hexadecyloxy)ethoxy)-2-oxido-1,4,2-dioxaphosphinan-5-yl)methyl)-4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)docosanamide MeSH Browser
- Organophosphonates MeSH
- Prodrugs MeSH
Even number fatty acid residues-docosanoyl (behenoyl) and stearoyl were selected for introduction to the N(4)-position of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMPC, cidofovir), and its 5-azacytosine counterpart, (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine) (HPMP-5-azaC) with the aim to prepare a new type of lipophilic prodrugs. The study on the influence of these modifications to the stability and biological activity of both antivirals was performed. Different reactivity of both systems towards acylation reactions was also found: the 4-NH2 group of cidofovir was more reactive compared to that of HPMP-5-azaC. In 5-azacytosine derivatives, we found mostly a destabilizing effect of the N(4)-acylation but this could be compensated by a positive influence of the esterification of the phosphonate group. Chemical stability of the 5-azacytosine moiety in the HPMP series is increasing in the following order: HPMP-5-azaC
References provided by Crossref.org
Synthesis of fluorinated acyclic nucleoside phosphonates with 5-azacytosine base moiety
