Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics
| Autor: | Schramm Vern L, Keith Clinch, Shivali A. Gulab, Jemy A. Gutierrez, Gary B. Evans, Jennifer M. Mason, Richard F.G. Fröhlich, Anthony D. Woolhouse, Peter C. Tyler |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adenosine
Pyrrolidines Stereochemistry Clinical Biochemistry Molecular Conformation Pharmaceutical Science Purine nucleoside phosphorylase Neisseria meningitidis Ribitol medicine.disease_cause Biochemistry Article Structure-Activity Relationship chemistry.chemical_compound Biomimetic Materials Transition state analog Drug Discovery Escherichia coli medicine Humans Structure–activity relationship Enzyme Inhibitors Methylene N-Glycosyl Hydrolases Molecular Biology Ions chemistry.chemical_classification Dose-Response Relationship Drug Organic Chemistry Enzyme Purine-Nucleoside Phosphorylase chemistry Molecular Medicine Amine gas treating |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:5181-5187 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.07.006 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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