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

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• 作者：Keith Clinch ; Gary B. Evans ; Richard F.G. Fr?hlich ; Shivali A. Gulab ; Jemy A. Gutierrez ; Jennifer M. Mason ; Vern L. Schramm ; Peter C. Tyler ; Anthony D. Woolhouse
• 关键词：Human MTAP ; Bacterial MTANs ; Ribooxacarbenium ion mimics ; Inhibitors ; Acyclic hydroxy-methylthio-amines
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 September, 2012
• 年：2012
• 卷：20
• 期：17
• 页码：5181-5187
• 全文大小：1139 K

文摘

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 K_i 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 [(¡À)-65 vs (¡À)-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.