Nucleosides. 5. Synthesis of guanine and formycin B derivatives as potential inhibitors of purine nucleoside phosphorylase

In an effort to develop potent human purine nucleoside phosphorylase (PNP) inhibitors as immunosuppressive and chemotherapeutic agents, several 8-aminoguanine derivatives were synthesized and evaluated as potential PNP inhibitors. These studies were designed to investigate the hydrophobic effect of...

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Veröffentlicht in:Journal of medicinal chemistry 1993-04, Vol.36 (8), p.1024-1031
Hauptverfasser: Chern, Ji Wang, Lee, Horng Yuh, Chen, Chien Shu, Shewach, Donna S, Daddona, Peter E, Townsend, Leroy B
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Sprache:eng
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Zusammenfassung:In an effort to develop potent human purine nucleoside phosphorylase (PNP) inhibitors as immunosuppressive and chemotherapeutic agents, several 8-aminoguanine derivatives were synthesized and evaluated as potential PNP inhibitors. These studies were designed to investigate the hydrophobic effect of a substituent on the N-9 of the purine heterocycle and/or the C-5' positions. Compounds such as 8-aminoguanosine, guanosine, formycin B, and 8-aminoacyclovir containing a p-(fluorosulfonyl)benzoyl moiety were synthesized. The affinity of these compounds to erythrocytic PNP was determined and none of these compounds showed a better affinity than those of the parent compounds. However, we found that the effect of hydrophobicity at the N-9 and the C-5' positions might play an important role in binding to the active site of PNP. Thus, 8-amino-5'-deoxy-5'-(phenylthio)guanosine (19) was found to be the best inhibitor in this series of compounds with a Ki = 0.45 microM.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00060a010