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 journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5326-5333
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number17
DOIs
StatePublished - Sep 1 2015

Fingerprint

Enantiomers
Methylthioinosine
Enzymes
Pharmaceutical Preparations
Purine-Nucleoside Phosphorylase
Phosphorylases
Bioactivity
Heterografts
Pseudomonas aeruginosa
Escherichia coli
Tumors
Neoplasms
5'-methylthioadenosine phosphorylase

Keywords

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

ASJC Scopus subject areas

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

Cite this

Evans, G. B., Cameron, S. A., Luxenburger, A., Guan, R., Suarez, J., Thomas, K., ... Tyler, P. C. (2015). Tight binding enantiomers of pre-clinical drug candidates. Bioorganic and Medicinal Chemistry, 23(17), 5326-5333. https://doi.org/10.1016/j.bmc.2015.07.059

Tight binding enantiomers of pre-clinical drug candidates. / Evans, Gary B.; Cameron, Scott A.; Luxenburger, Andreas; Guan, Rong; Suarez, Javier; Thomas, Keisha; Schramm, Vern L.; Tyler, Peter C.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 17, 01.09.2015, p. 5326-5333.

Research output: Contribution to journalArticle

Evans, GB, Cameron, SA, Luxenburger, A, Guan, R, Suarez, J, Thomas, K, Schramm, VL & Tyler, PC 2015, 'Tight binding enantiomers of pre-clinical drug candidates', Bioorganic and Medicinal Chemistry, vol. 23, no. 17, pp. 5326-5333. https://doi.org/10.1016/j.bmc.2015.07.059
Evans GB, Cameron SA, Luxenburger A, Guan R, Suarez J, Thomas K et al. Tight binding enantiomers of pre-clinical drug candidates. Bioorganic and Medicinal Chemistry. 2015 Sep 1;23(17):5326-5333. https://doi.org/10.1016/j.bmc.2015.07.059
Evans, Gary B. ; Cameron, Scott A. ; Luxenburger, Andreas ; Guan, Rong ; Suarez, Javier ; Thomas, Keisha ; Schramm, Vern L. ; Tyler, Peter C. / Tight binding enantiomers of pre-clinical drug candidates. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 17. pp. 5326-5333.
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