Abstract
As part of a project aimed at identifying effective low molecular weight nonphosphorus monoanionic inhibitors of PTPs, we have synthesized 4-[(5-arylidene-4-oxo-2-phenyliminothiazolidin-3-yl)methyl]benzoic acids (4) and evaluated their inhibitory activity against human PTP1B and LMW-PTP enzymes. The introduction of a 2-phenylimino moiety onto the 4-thiazolidinone ring was designed to enhance the inhibitor/enzyme affinity by means of further favourable interactions with residues of the active site and the surrounding loops. Some of the compounds (4a-d, f) showed interesting inhibition levels in the low micromolar range. The 5-arylidene moiety of acids 4 proved to markedly influence the potency of these inhibitors. Molecular modeling experiments inside the binding sites of both enzymes were performed.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Benzoates / chemical synthesis
-
Benzoates / pharmacology
-
Computer Simulation
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology*
-
Humans
-
Molecular Weight
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
-
Protein Tyrosine Phosphatases / antagonists & inhibitors*
-
Protein Tyrosine Phosphatases / metabolism
-
Proto-Oncogene Proteins / antagonists & inhibitors*
-
Proto-Oncogene Proteins / metabolism
-
Thiazolidines / chemical synthesis*
-
Thiazolidines / pharmacology*
Substances
-
Benzoates
-
Enzyme Inhibitors
-
Proto-Oncogene Proteins
-
Thiazolidines
-
ACP1 protein, human
-
PTPN1 protein, human
-
Protein Tyrosine Phosphatase, Non-Receptor Type 1
-
Protein Tyrosine Phosphatases