Synthesis of second-generation transition state analogues of human purine nucleoside phosphorylase.
Purine nucleoside phosphorylases (PNPs) catalyze nucleophilic displacement reactions by migration of the cationic ribooxacarbenium carbon between the fixed purine and phosphate nucleophiles. As the phosphorolysis reaction progresses along the reaction coordinate, the distance between the purine and carbocation increases and the distance between carbocation and phosphate anion decreases. Immucillin-H and Immucillin-G have been shown previously to be potent inhibitors of PNP. We now report the synthesis of a second generation of stable transition state analogues, DADMe-Immucillins 2, 3, and 4, with increased distance between ribooxacarbenium and purine mimics by incorporation of a methylene bridge between these groups. These compounds are potent inhibitors with equilibrium dissociation constants as low as 7 pM against human PNP. Stable chemical analogues of enzymatic transition states are necessarily imperfect since they lack the partial bond character of the transition state. The immucillins and DADMe-Immucillins represent approaches from the product and reaction side of the transition state.
Evans
Gary B
GB
Carbohydrate Chemistry Team, Industrial Research Limited, PO Box 31310, Lower Hutt, New Zealand. g.evans@irl.cri.nz
Furneaux
Richard H
RH
Lewandowicz
Andrzej
A
Schramm
Vern L
VL
Tyler
Peter C
PC
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D019271:Hypoxanthine / Q000138:chemical synthesis* / Q000737:chemistry; D007042:Hypoxanthines; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
C479894:1-((8-aza-9-deazahypoxanthin-9-yl)methyl)-3-hydroxy-4-hydroxymethylpyrrolidine; C479893:1-((9-deazaguanin-9-yl)methyl)-3-hydroxy-4-hydroxymethylpyrrolidine; C479892:1-((9-deazahypoxanthin-9-yl)methyl)-3-hydroxy-4-hydroxymethylpyrrolidine; D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D011759:Pyrrolidines; D019271:Hypoxanthine; D006147:Guanine; D011683:Purine-Nucleoside Phosphorylase