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

Org Biomol Chem. 2014 Oct 28;12(40):7971-82. doi: 10.1039/c4ob01332h. Epub 2014 Sep 1.

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; K = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / antagonists & inhibitors*
  • 5'-Nucleotidase / metabolism
  • Cytosol / enzymology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Mitochondria / enzymology*
  • Molecular Conformation
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Organophosphonates
  • 5'(3')-nucleotidase
  • 5'-Nucleotidase