Issue 16, 2015

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

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.

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

Supplementary files

Article information

Article type
Paper
Submitted
16 Jan 2015
Accepted
12 Mar 2015
First published
13 Mar 2015
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2015,13, 4693-4705

Author version available

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

R. Pohl, L. Poštová Slavětínská, W. S. Eng, D. T. Keough, L. W. Guddat and D. Rejman, Org. Biomol. Chem., 2015, 13, 4693 DOI: 10.1039/C5OB00097A

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