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1,3‐Disubstituted‐4‐Aminopyrazolo [3, 4‐d] Pyrimidines, a New Class of Potent Inhibitors for Phospholipase D
Author(s) -
Kulkarni Aditya,
Quang Phong,
Curry Victoriana,
Keyes Renee,
Zhou Weihong,
Cho Hyejin,
Baffoe Jonathan,
Török Béla,
Stieglitz Kimberly
Publication year - 2014
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12319
Subject(s) - phospholipase d , biochemistry , enzyme , phospholipase , phosphatidic acid , pld2 , phospholipase c , phospholipase a2 , chemistry , phospholipase a , phospholipid , biology , membrane
Phospholipase D enzymes cleave lipid substrates to produce phosphatidic acid, an important precursor for many essential cellular molecules. Phospholipase D is a target to modulate cancer‐cell invasiveness. This study reports synthesis of a new class of phospholipase D inhibitors based on 1,3‐disubstituted‐4‐amino‐pyrazolopyrimidine core structure. These molecules were synthesized and used to perform initial screening for the inhibition of purified bacterial phospholipase D, which is highly homologous to the human PLD 1 . Initially tested with the bacterial phospholipase D enzyme, then confirmed with the recombinant human PLD 1 and PLD 2 enzymes, the molecules presented here exhibited inhibition of phospholipase D activity ( IC 50 ) in the low‐nanomolar to low‐micromolar range with both monomeric substrate diC 4 PC and phospholipid vesicles and micelles. The data strongly indicate that these inhibitory molecules directly block enzyme/vesicle substrate binding. Preliminary activity studies using recombinant human phospholipase Ds in in vivo cell assays measuring both transphosphatidylation and head‐group cleavage indicate inhibition in the mid‐ to low‐nanomolar range for these potent inhibitory novel molecules in a physiological environment.