- Selective Inhibitors of Helicobacter pylori Methylthioadenosine Nucleosidase and Human Methylthioadenosine Phosphorylase
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Bacterial 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) hydrolyzes adenine from its substrates to form S-methyl-5-thioribose and S-ribosyl-l-homocysteine. MTANs are involved in quorum sensing, menaquinone synthesis, and 5′-methylthioadenosine recycling to S-adenosylmethionine. Helicobacter pylori uses MTAN in its unusual menaquinone pathway, making H. pylori MTAN a target for antibiotic development. Human 5′-methylthioadenosine phosphorylase (MTAP), a reported anticancer target, catalyzes phosphorolysis of 5′-methylthioadenosine to salvage S-adenosylmethionine. Transition-state analogues designed for HpMTAN and MTAP show significant overlap in specificity. Fifteen unique transition-state analogues are described here and are used to explore inhibitor specificity. Several analogues of HpMTAN bind in the picomolar range while inhibiting human MTAP with orders of magnitude weaker affinity. Structural analysis of HpMTAN shows inhibitors extending through a hydrophobic channel to the protein surface. The more enclosed catalytic sites of human MTAP require the inhibitors to adopt a folded structure, displacing the phosphate nucleophile from the catalytic site.
- Harijan, Rajesh K.,Hoff, Oskar,Ducati, Rodrigo G.,Firestone, Ross S.,Hirsch, Brett M.,Evans, Gary B.,Schramm, Vern L.,Tyler, Peter C.
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supporting information
p. 3286 - 3296
(2019/04/17)
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- Certain 3,9-dideazapurines as inhibitors of purine nucleoside phosphorylase
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The synthesis of four 3,9-dideazapurines is described. In order to achieve the desired substitution pattern, a new approach to the pyrrolo[2,3- c]pyridine ring system was devised utilizing the Gassman reaction as the key step for its construction. The four target heterocycles were all evaluated for their ability to inhibit human erythrocytic purine nucleoside phosphorylase.
- Rose, Jerry D.,Secrist III, John A.,Montgomery, John A.
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p. 2443 - 2461
(2007/10/03)
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