DADMe-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... 

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 7-11. 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... 

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... 

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