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1999[X]
1Author    Agnieszka Bzowska3, Lucyna Magnowska3, Zygmunt KazimierczukbRequires cookie*
 Title    Synthesis of 6-Aryloxy-and 6-Arylalkoxy-2-chloropurines and Their Interactions with Purine Nucleoside Phosphorylase from Escherichia coli  
 Abstract    The phase transfer method was applied to perform the nucleophilic substitution of 2,6-dichloropurines by modified arylalkyl alcohol or phenols. Since under these conditions only the 6-halogen is exchanged, this method gives 2-chloro-6-aryloxy-and 2-chloro-6-arylalkoxy-purines. 2-Chloro-6-benzylthiopurine was synthesized by alkylation of 2-chloro-6-thiopurine with benzyl bromide. The stereoisom ers of 2-chloro-6-(l-phenyl-l-ethoxy)purine were ob­ tained from R-and 5-enantiomers of sec.-phenylethylalcohol and 2,6-dichloropurine. A ll derivatives were tested for inhibition with purified hexameric E. coli purine nucleoside phosphorylase (PNP). For analogues showing IC50 < 10 ^.m, the type o f inhibition and inhibi­ tion constants were determined. In all cases the experimental data were best described by the mixed-type inhibition model and the uncompetitive inhibition constant, Kiu, was found to be several-fold lower than the competitive inhibition constant, Kic. This effect seems to be due to the 6-aryloxy-or 6-arylalkoxy substituent, because a natural PNP substrate adenine, as well as 2-chloroadenine, show mixed type inhibition with almost the same inhibition con­ stants Kiu and K1C . The most potent inhibition was observed for 6-benzylthio-2-chloro-, 6-benzyloxy-2-chloro-, 2-chloro-6-(2-phenyl-l-ethoxy), 2-chloro-6-(3-phenyl-l-propoxy)-and 2-chloro-6-ethoxypur-ines (Kiu = 0.4, 0.6, 1.4, 1.4 and 2.2 [im, respectively). The i?-stereoisomer o f 2-chloro-6-(l-pheny-l-ethoxy)purine has Kiu = 2.0 ^im, whereas inhibition o f its S counterpart is rather weak (IC50> 12 jim). More rigid (e.g. phenoxy-), non-planar (cyclohexyloxy-), or more bulky (2,4,6-trimethylphenoxy-) substituents at position 6 of the purine base gave less potent inhibi­ tors (IC50 = 26, 56 and >100 [im, respectively). The derivatives are selective inhibitors of hexameric "high-molecular mass" PNPs because no inhibitory activity vs. trimeric Cellulomo-nas sp. PNP was detected. By establishing the ligand-dependent stabilization pattern of the E. coli PNP it was shown that the new derivatives, similarly as the natural purine bases, are able to form a dead-end ternary complex with the enzyme and orthophosphate. It was also shown that the derivatives are substrates in the reverse synthetic direction catalyzed by E. coli PNP 
  Reference    Z. Naturforsch. 54c, 1055—1067 (1999); received May 31/August 2 1999 
  Published    1999 
  Keywords    2-Chloropurines, Purine Nucleoside Phosphorylase, Inhibition, Escherichia coli, Phase Transfer Reactions 
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 TEI-XML for    default:Reihe_C/54/ZNC-1999-54c-1055.pdf 
 Identifier    ZNC-1999-54c-1055 
 Volume    54