Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring

Pohl, Radek, Slavetinska, Lenka Postova, Eng, Wai Soon, Keough, Dianne T., Guddat, Luke W. and Rejman, Dominik (2015) Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring. Organic and Biomolecular Chemistry, 13 16: 4693-4705. doi:10.1039/c5ob00097a


Author Pohl, Radek
Slavetinska, Lenka Postova
Eng, Wai Soon
Keough, Dianne T.
Guddat, Luke W.
Rejman, Dominik
Title Synthesis, conformational studies, and biological properties of phosphonomethoxyethyl derivatives of nucleobases with a locked conformation via a pyrrolidine ring
Journal name Organic and Biomolecular Chemistry   Check publisher's open access policy
ISSN 1477-0520
1477-0539
Publication date 2015-04-28
Sub-type Article (original research)
DOI 10.1039/c5ob00097a
Open Access Status DOI
Volume 13
Issue 16
Start page 4693
End page 4705
Total pages 13
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
Abstract 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Thu, 18 Jun 2015, 22:33:46 EST by Anthony Yeates on behalf of School of Chemistry & Molecular Biosciences