This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-d]pyrimidine (APP) nucleus and their evaluation as inhibitors of ADA from bovine spleen. The 2-substituted aminopyrazolopyrimidines proved to be potent inhibitors, most of them exhibiting Ki values in the nanomolar/subnanomolar range. In this series the inhibitory activity is enhanced with the increase in length of the alkyl chain, reaching a maximum with the n-decyl substituent. Insertion of a 2′-hydroxy group in the ra-decyl chain gave 3k, whose (R)-isomer displayed the highest inhibitory potency of the series (Ki 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (Ki 1.14 nM), which was taken as the reference standard. Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors

Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-d]pyrimidine Ring System. Synhesis, Structure-Activity Relationships, and Molecular Modeling Studies

DA SETTIMO PASSETTI, FEDERICO;LA MOTTA, CONCETTINA;TALIANI, SABRINA;SIMORINI, FRANCESCA;MARINI, ANNA MARIA;MARTINI, CLAUDIA
2005

Abstract

This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-d]pyrimidine (APP) nucleus and their evaluation as inhibitors of ADA from bovine spleen. The 2-substituted aminopyrazolopyrimidines proved to be potent inhibitors, most of them exhibiting Ki values in the nanomolar/subnanomolar range. In this series the inhibitory activity is enhanced with the increase in length of the alkyl chain, reaching a maximum with the n-decyl substituent. Insertion of a 2′-hydroxy group in the ra-decyl chain gave 3k, whose (R)-isomer displayed the highest inhibitory potency of the series (Ki 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (Ki 1.14 nM), which was taken as the reference standard. Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors
DA SETTIMO PASSETTI, Federico; Primofiore, G; LA MOTTA, Concettina; Taliani, Sabrina; Simorini, Francesca; Marini, ANNA MARIA; Mugnaini, L; Lavecchia, A; Novellino, E; Tuscano, D; Martini, Claudia
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/204866
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