Back to Search
Start Over
Synthesis and PTP Inhibitory Activity of Illudalic Acid and Its Methyl Ether, with Insights into Selectivity for LAR PTP over Other Tyrosine Phosphatases under Physiologically Relevant Conditions
- Source :
- Journal of Natural Products. 82:3386-3393
- Publication Year :
- 2019
- Publisher :
- American Chemical Society (ACS), 2019.
-
Abstract
- The protein tyrosine phosphatase (PTP) family of enzymes includes many attractive therapeutic targets, such as those in the leukocyte common antigen-related (LAR) subfamily of receptor PTPs. Synthesis and PTP inhibitory activity of illudalic acid and its methyl ether are described, with a focus on selective inhibition of LAR PTP relative to a small collection of other representative PTPs. The synthesis comprises 16 steps and provides illudalic acid in up to 12% overall yield from neopentylene-fused benzoate 1 (20 steps from commercial materials). Illudalic acid dose-dependently (measured IC50 = 2.1 ± 0.2 μM) and time-dependently inhibits LAR consistent with previous reports of covalent binding. The kinetics of LAR inhibition by illudalic acid are consistent with a two-step mechanism in which the inhibitor and enzyme first interact noncovalently (KI = 130 ± 50 μM), followed by covalent ligation at a rate kinact = 1.3 ± 0.4 min-1. The kinact/KI ratio of 104 corresponds to a t∞1/2 of 0.5 min, as discussed herein. The phenol methyl ether of illudalic acid was found to be less potent in our dose-response assays (measured IC50 = 55 ± 6 μM) but more selective for LAR, with a weaker initial noncovalent interaction and faster covalent ligation of LAR as compared to illudalic acid itself. A truncated analogue of illudalic acid that lacks the neopentylene ring fusion was found to be devoid of significant activity under our assay conditions, in contrast to previous reports. These observations collectively help inform further development of illudalic acid analogues as potent and selective inhibitors of the LAR subfamily of tyrosine phosphatases.
- Subjects :
- Methyl Ethers
Phosphatase
Pharmaceutical Science
Ether
Protein tyrosine phosphatase
01 natural sciences
Analytical Chemistry
chemistry.chemical_compound
Coumarins
Drug Discovery
Humans
Enzyme Inhibitors
Tyrosine
Receptor
IC50
Pharmacology
chemistry.chemical_classification
Dose-Response Relationship, Drug
010405 organic chemistry
Spectrum Analysis
Organic Chemistry
0104 chemical sciences
010404 medicinal & biomolecular chemistry
Enzyme
Complementary and alternative medicine
chemistry
Biochemistry
Covalent bond
Molecular Medicine
Protein Tyrosine Phosphatases
Subjects
Details
- ISSN :
- 15206025 and 01633864
- Volume :
- 82
- Database :
- OpenAIRE
- Journal :
- Journal of Natural Products
- Accession number :
- edsair.doi.dedup.....51f56f8ef699772e02e88d0fe551fee2