Immucillin

Examples of fluorine-containing imino sugars as partial structures of PNPs have been reported. The S -deoxy-S -fluoro compound 116 ( S -F-Imucillin H, Scheme 29) was found to be a nanomolar inhibitor of human PNP (1 nM) as well as that of Plasmodium falciparum (A) 60 nM).237 2,-Deoxy-2,2 -difluoro derivative 117 ( -diF-immucillin-H ) exhibited slightly more inhibitory power against the microbial enzyme and an enhanced selectivity of more than three orders of magnitude (ATj 1.4 nM vs. 15 pM).238 Another type of inhibitor, the 3-fluoro compound 118 ( F-DADMe-immucillin-H ) was shown a potent picomolar inhibitor of the human enzyme (Kf 32 pM), with some selectivity over the Plasmodium phos-phorylase (2.6 nM), whereas the enantiomer 119 was 50- to 100-fold less active 239,240... 

Exceptional in their activities are the fluorine-containing immucillins. Clearly, the additional structural features of the aglycon contribute strongly to their inhibitory power. 

Immucillin-H (167, 72 pM) complexed with human PNP (PDB 1PF7) provided... 

P. falciparum in complex with immucillin-H and sulfate (Kd 0.86 nM PDB 1NW4) as well as with phosphate (PDB 1RR6) and the complex with 5 -deoxy-5 -methylthio-immucillin-H (169, Kd 2.7 nM PDB 1Q1G) were reported in 2004.330 MT-immucil-lin-H 73 (Scheme 19) was the first inhibitor found with specificity for the malarial enzyme. 

V. Singh, W. Shi, G. B. Evans, P. C. Tyler, R. H. Fumeaux, S. C. Almo, and V. L. Schramm, Picomolar transition state analogue inhibitors of human 5 -methylthioadenosine phosphorylase and X-ray stmcture with MT-immucillin-A, Biochemistry, 43 (2004) 9-18. 

Crystallographic analysis has been used quite effectively to solidify structural determinations. Several examples include dihydrofolate reductase complexes , nucleosides <1999AXC1335, 1999AXC1560>, zopi-clone <2001CC2204>, and immucillin inhibitors <2003BBR917>. 

A class of compounds, called immucillins <2003BBR917>, are potent transition-state analogs of purine nucleoside phosphorylase. As such these pyrrolo[3,2-4 pyrimidines have been the target of much exploration. 

Figure 7-9. Oxacarbenium ion transition state, Immucillin-H and DADMe-Immucillin-H are shown. The nomenclature - DADMe is (4 -Deaza-l -Aza-2/-Deoxy-l/,N-9-Methylene)-Immucillin-H. On die right, the molecular electrostatic potential surfaces (MEP) for the oxacarbenium/hypoxanthine pair at die transition state, Immucillin-H and DADMe-Immucillin-H are shown. MEP were calculated at HF/STO-3G theory level for optimized geometry at BlLYP/6-31G(d) theory level and visualized by Molekel 4.0 at electron density of 0.008 electron/bohr...

Figure 7-10. Immucillin transition state analogues and their corresponding DADMe-modifications. Initial (Kj) or slow-onset equilibrium dissociation constants (Kj ), are shown for human (bold) and P. falciparum PNP (italic)...

A. The DADMe modification also provides a favorable charge localization to place the cation at the l -position. The pKa of l -pyrrolidine nitrogen in DADMe system is 8.575 and provides the cationic nitrogen to ion pair with phosphate in the active site of phosphorylases. The N4 nitrogen of Immucillin-H has a pKa of 6.972 and is cationic in the active site, however the Cl -C9 distance is only... 

Figure 7-11. 5 -p-Cl-phenylthio-DADMe-Immucillin-A is a femtomolar transition state analogue for E.coli 5 -methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN). Initial (Kj) and equilibrium (Kf) dissociation constant are shown... 

Kicska GA, Tyler PC, Evans GB, Furneaux RH, Schramm VL, Kim K (2003) Purine-less death in Plasmodium falciparum induced by Immucillin-H, a transition state analogue of purine nucleoside phosphorylase. J. Biol. Chem. 277 3226-3231... 

FIGURE 1.15 A synthetic Lewis blood group deteiminant/ceramide antigen (45) and the synthetic specific enzyme inhibitor immucillin H (46). 

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