Jump to main content
Jump to site search

Issue 40, 2014
Previous Article Next Article

Conformationally constrained nucleoside phosphonic acids – potent inhibitors of human mitochondrial and cytosolic 5′(3′)-nucleotidases

Author affiliations

Abstract

This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5′(3′)-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-D-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; KmdNi = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, KcdNi = 11.60 μM; iodoxy derivative, KcdNi = 6.60 μM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.

Graphical abstract: Conformationally constrained nucleoside phosphonic acids – potent inhibitors of human mitochondrial and cytosolic 5′(3′)-nucleotidases

Back to tab navigation

Supplementary files

Publication details

The article was received on 27 Jun 2014, accepted on 13 Aug 2014 and first published on 13 Aug 2014


Article type: Paper
DOI: 10.1039/C4OB01332H
Citation: Org. Biomol. Chem., 2014,12, 7971-7982
  •   Request permissions

    Conformationally constrained nucleoside phosphonic acids – potent inhibitors of human mitochondrial and cytosolic 5′(3′)-nucleotidases

    O. Šimák, P. Pachl, M. Fábry, M. Buděšínský, T. Jandušík, A. Hnízda, R. Skleničková, M. Petrová, V. Veverka, P. Řezáčová, J. Brynda and I. Rosenberg, Org. Biomol. Chem., 2014, 12, 7971
    DOI: 10.1039/C4OB01332H

Search articles by author

Spotlight

Advertisements