Tight binding enantiomers of pre-clinical drug candidates

Bioorg Med Chem. 2015 Sep 1;23(17):5326-33. doi: 10.1016/j.bmc.2015.07.059. Epub 2015 Jul 30.

Abstract

MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.

Keywords: Cancer; Drug; Enantiomer; Enzyme; Transition state analogue.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • Adenine / pharmacology
  • Drug Discovery
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology*
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Neoplasms / enzymology
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protein Binding
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / enzymology*
  • Purine-Nucleoside Phosphorylase / antagonists & inhibitors*
  • Purine-Nucleoside Phosphorylase / metabolism
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacology*
  • Stereoisomerism

Substances

  • Pyrrolidines
  • methylthio-DADMe-immucillin-A
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • Adenine