Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics

Keith Clinch, Gary B. Evans, Richard F G Fröhlich, Shivali A. Gulab, Jemy A. Gutierrez, Jennifer M. Mason, Vern L. Schramm, Peter C. Tyler, Anthony D. Woolhouse

Research output: Contribution to journalArticle

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Abstract

Several acyclic hydroxy-methylthio-amines with 3-5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and Escherichia coli and Neisseria meningitidis MTANs and gave Ki values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4- methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon-carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts.

Original languageEnglish (US)
Pages (from-to)5181-5187
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number17
DOIs
StatePublished - Sep 1 2012

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adenosylhomocysteine nucleosidase
Carbon
Ions
Escherichia coli
Amines
Purine-Nucleoside Phosphorylase
Methylation
Neisseria meningitidis
Enzymes
Derivatives
Atoms
1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthioribitol
5'-methylthioadenosine phosphorylase

Keywords

  • Acyclic hydroxy-methylthio-amines
  • Bacterial MTANs
  • Human MTAP
  • Inhibitors
  • Ribooxacarbenium ion mimics

ASJC Scopus subject areas

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

Cite this

Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics. / Clinch, Keith; Evans, Gary B.; Fröhlich, Richard F G; Gulab, Shivali A.; Gutierrez, Jemy A.; Mason, Jennifer M.; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 17, 01.09.2012, p. 5181-5187.

Research output: Contribution to journalArticle

Clinch, Keith ; Evans, Gary B. ; Fröhlich, Richard F G ; Gulab, Shivali A. ; Gutierrez, Jemy A. ; Mason, Jennifer M. ; Schramm, Vern L. ; Tyler, Peter C. ; Woolhouse, Anthony D. / Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 17. pp. 5181-5187.
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T1 - Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics

AU - Clinch, Keith

AU - Evans, Gary B.

AU - Fröhlich, Richard F G

AU - Gulab, Shivali A.

AU - Gutierrez, Jemy A.

AU - Mason, Jennifer M.

AU - Schramm, Vern L.

AU - Tyler, Peter C.

AU - Woolhouse, Anthony D.

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KW - Inhibitors

KW - Ribooxacarbenium ion mimics

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