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

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 K i values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1 S )-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio- d -ribitol (MT-Immucillin-A, 3 ) and (3 R ,4 S )-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.