PMID: 6991691Apr 1, 1980Paper

Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. 1. 7-Substituted 6-oxopurines

Journal of Medicinal Chemistry
J R PiperJ A Montgomery

Abstract

Biological evidence indicates that the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) is vital for cell proliferation in malarial parasites but nonessential for mammalian cells. 7-Substituted guanines and hypoxanthines in which the 7 substituent bears functional or hydrophobic groups were prepared with the aim of finding a suitably constituted compound whose resemblance to the normal substrate allows it to compete for the reversible purine binding site of HGRPTase while allowing a substituent group of the inhibitor molecule to form a covalent bond or strong hydrophobic bond with appropriate sites on the enzyme. Multistep syntheses that began with hydroxyalkylations and alkylations of guanosine led to four key guanines substituted at the 7 position by the following chains: 2-aminoethyl, 3-amino-2-hydroxypropyl, 3-aminobenzyl, and 4-aminobenzyl. Similarly, 7-(4-aminobenzyl)hypoxanthine was prepared. Reactions at the side-chain amino groups with bromoacetic anhydride (or, alternatively, 4-nitrophenyl bromoacetate) and 3- and 4-(fluorosulfonyl)benzoyl chlorides afforded derivatives bearing functional groups capable of forming covalent bonds with enzymes through displacement reactions. 4-Chlorobenzyl derivatives ...Continue Reading

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