Tight binding enantiomers of pre-clinical drug candidates

Gary B. Evans, Scott A. Cameron, Andreas Luxenburger, Rong Guan, Javier Suarez, Keisha Thomas, Vern L. Schramm, Peter C. Tyler

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5326-5333
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number17
StatePublished - Sep 1 2015


  • Cancer
  • Drug
  • Enantiomer
  • Enzyme
  • Transition state analogue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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