title: 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 (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.
authors.affiliation: Carbohydrate Chemistry, Industrial Research Limited, PO Box 31310, Lower Hutt 5040, New Zealand. k.clinch@irl.cri.nz
authors.forename: Keith
authors.initials: K
authors.lastname: Clinch
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Richard F G
authors.initials: RF
authors.lastname: Fröhlich
authors.forename: Shivali A
authors.initials: SA
authors.lastname: Gulab
authors.forename: Jemy A
authors.initials: JA
authors.lastname: Gutierrez
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Mason
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
authors.forename: Peter C
authors.initials: PC
authors.lastname: Tyler
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Woolhouse
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007477:Ions / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009345:Neisseria meningitidis / Q000201:enzymology; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C577030:1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthioribitol; C577031:1-(9-deazaadenin-9-yl)methyl-3-hydroxy-4-methylthiomethylpyrrolidine; D004791:Enzyme Inhibitors; D007477:Ions; D011759:Pyrrolidines; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D009699:N-Glycosyl Hydrolases; C019606:adenosylhomocysteine nucleosidase; D000241:Adenosine