Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring
Language English Country Great Britain, England Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25798893
DOI
10.1039/c5ob00097a
Knihovny.cz E-resources
- MeSH
- Adenine chemistry MeSH
- Antimalarials chemical synthesis MeSH
- Chemistry, Pharmaceutical MeSH
- Hypoxanthine chemistry MeSH
- Kinetics MeSH
- Hydrogen-Ion Concentration MeSH
- Protein Conformation MeSH
- Oxygen chemistry MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Organophosphonates chemistry MeSH
- Pentosyltransferases antagonists & inhibitors MeSH
- Plasmodium falciparum drug effects MeSH
- Pyrrolidines chemistry MeSH
- Drug Design MeSH
- Hydrogen Bonding MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Adenine MeSH
- Antimalarials MeSH
- Hypoxanthine MeSH
- Oxygen MeSH
- Organophosphonates MeSH
- Pentosyltransferases MeSH
- purine phosphoribosyltransferase MeSH Browser
- Pyrrolidines MeSH
Systematic structure-activity studies on a diverse family of nucleoside phosphonic acids has led to the development of potent antiviral drugs such as HPMPC (CidofovirTM), PMEA (AdefovirTM), and PMPA (TenofovirTM), which are used in the treatment of CMV-induced retinitis, hepatitis B, and HIV, respectively. Here, we present the synthesis of a novel class of acyclic phosphonate nucleotides that have a locked conformation via a pyrrolidine ring. NMR analysis of these compounds revealed that the pyrrolidine ring has a constrained conformation when in the cis-form at pD < 10 via hydrogen bonding. Four of these compounds were tested as inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases. The most potent has a Ki of 0.6 μM for Plasmodium falciparum HGXPRT.
References provided by Crossref.org
Molecular mutagenesis of ppGpp: turning a RelA activator into an inhibitor
