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Document completely by adding any of several chemical groupings to the benzene ring. The best fit came from adding a chlorine atom to position 3 of the benzene ring. C. Phosphate Site Page 164 The final step added a group that would interact with the phosphate binding site either directly or via electrostatic interactions. We could not use phosphate itself, because phosphate-containing compounds are not metabolically stable and have difficulty passing through cell membranes intact. Acyclovir diphosphate, which is not membrane permeable and is subject to extracellular metabolism, is a good example. Our results suggested that an ideal PNP inhibitor in the 9-deazapurine series would contain an aromatic group and a substituent with affinity for the phosphate site interlinked by spacers with optimum lengths. Crystallographic and modeling studies suggested a two-to-four-atom spacer. Initial modeling studies encouraged us to prepare several structures, but they failed to improve the binding affinity of our twopart structure. Crystallographic analysis of a number of PNP inhibitor complexes revealed significant displacement of the inhibitors. These displacements appear to be the result of close contacts between the inhibitor and the ion in the phosphate binding site. Sulfate ions occupy the phosphate site in PNP crystals as they are grown from ammonium sulfate solution. These inhibitors were more potent when the binding was measured in 1 mM phosphate solution rather than in 50 mM phosphate. Kinetic studies showed that these inhibitors were competitive not only with inosine but also with phosphate, in keeping with the above observation. These results, summarized in Table 1, show that the IC 50 (50 mM) is equal to or larger than the IC 50 (1 mM), in some cases by as much as 100-fold. The ratio and the dimension of the 9-substituent show some correlation. Compounds such as 8-aminoguanosine and 8-amino-9-(2-thienylmethyl)guanine show no difference. Since the concentration of phosphate in intact cells is 1 mM, we routinely used this assay condition for all PNP inhibitors. Starting with a model of the 9-benzyl-9-deazaguanine/PNP complex, we concluded that two of the positions on the 9-benzyl group, namely the 2-position of the phenyl ring and one of the benzylic sites, appeared to be oriented so that a group attached to either one could interact favorably with the phosphate binding site. The first compound made in this series, 9-[2-(3-phosphonopropoxy)benzyl]guanine, turned out to be a poor PNP inhibitor. Subsequent crystallographic analysis revealed that the plane of the aromatic ring had rotated approximately 90° from its optimum position in the hydrophobic pocket. This reorientation of the ring was presumably necessary to accommodate the four atom spacer between the phenyl ring and the phosphonate group. A compound http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_164.html [4/5/2004 5:02:25 PM]
Document Table 1 Inhibition Data for Selected PNP Inhibitors by Increasing IC 50 Value R 2a R 2 IC 50, μM Ratio d 50 mM phosphate b 1 mM phosphate c (S)-3-Chlorophenyl CH 2CO 2H 0.031 0.0059 5.3 3-Chlorophenyl CH 2CN 1.8 0.010 180 2-Tetrehydrothienyl H 0.22 0.011 20 3,4-Dichlorophenyl H 0.25 0.012 21 3-Thienyl H 0.08 0.020 4 3-Trifluoromethylcyclohexyl H 0.74 0.020 37 Cyclopentyl H 1.8 0.029 62 Cycloheptyl H 0.86 0.030 29 Pyridin-3-yl H 0.20 0.030 7.3 2-(Phosphonoethyl)phenyl e H 0.45 0.035 13 Cyclohexyl H 2.0 0.043 47 2-Furanyl H 0.31 0.085 3.6 (R)-3-Chlorophenyl CH 2CO 2H 0.90 0.16 5.6 2-Phosphonopropoxyphenyl e H 42 1.0 42 a Compounds with R2 not equal to H are racemic mixtures unless the R or S isomer is designated. b Calf spleen PNP assayed in 50 mM phosphate buffer. c Calf spleen PNP assayed in 1 mM phosphate buffer. d IC50 at 50 mM phosphate divided by IC 50 at 1 mM phosphate. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_165.html (1 of 2) [4/5/2004 5:02:28 PM] Page 165
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Page 187 and 188: Document We determined the structur
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Page 195 and 196: Document large solvent channels and
Page 197 and 198: Document IV. Drug Design Progressio
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Page 205 and 206: Document References 1. Parks RE Jr.
Page 207 and 208: Document 17. Ealick SE, Rule SA, Ca
Page 209 and 210: Document 6 Structural Implications
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Page 215 and 216: Document Page 176 0.43 Å) as the c
Page 217 and 218: Document Page 178 studies show that
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Document 17 Structure and Functiona
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document II. Type IFNs A great deal
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Document Page 441 sequence of the m
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Document Page 443 that allowed for
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Document Page 476 nM, respectively.
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document [Protease targets] serinyl
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