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

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 IC 50 = 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 (K I = 130 ± 50 μM), followed by covalent ligation at a rate k inact = 1.3 ± 0.4 min −1 . The k inact /K I ratio of 10 4 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 IC 50 = 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.

Terminalin from African Mango (Irvingia gabonensis) Stimulates Glucose Uptake through Inhibition of Protein Tyrosine Phosphatases

“…Some PTPs, including PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, are associated with type 2 diabetes; therefore, recognition of agents that can inhibit PTPs may be a strategy to identify promising drugs with antidiabetic properties. Many natural products have been identified to treat or prevent various human diseases via inhibition of PTPs, for instance, illudalic acid inhibited the catalytic activity of human leukocyte common antigen-related PTP involved in the pathogenesis of insulin resistance [ 6 , 36 ]. To identify the targets of terminalin, PTPN1, PTPN9, PTPN11, PTPRF, and PTPRS were overexpressed in Escherichia coli and purified using a cobalt-affinity resin.…”

Small Molecules Targeting PTPσ–Trk Interactions Promote Sympathetic Nerve Regeneration

“…1 H NMR (400 MHz, chloroform-d): δ H (ppm) = 7.31 (s, 1H), 6.13 (s, 1H), 5.57 (br, 2H), 3.91 (t, J = 6.9 Hz, 2H), 3.84 (s, 6H), 1.79 (t, J = 7.6 Hz, 2H), 1.52− 1.39 (m, 2H), 1.34 (m, 4H), 0.91 (d, J = 7.0 Hz, 3H). 13 Methyl 2-acrylamido-5-(hexyloxy)-4-methoxybenzoate (4-2). Methyl 2-amino-5-(hexyloxy)-4-methoxybenzoate (3-2) (197 mg, 0.70 mmol) was dissolved in DCM (5 mL) followed by the addition of acryloyl chloride (76 mg, 0.84 mmol) at 0 °C.…”

“…1 (m, 4H), 1.02−0.77 (m, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ C (ppm) = 168.66, 164. 18, 154.64, 143.64, 137.72, 132.52, 127.31, 113.99, 106.76, 103.68, 69.51, 56.23, 52.25, 31.71, 29.83, 29.22, 25.76, 22.71, 14.17.…”

Synthesis of Illudinine from Dimedone and Identification of Activity as a Monoamine Oxidase Inhibitor

“…Figure ). The various illudalane sesquiterpenes have been popular targets for target-oriented synthesis, especially in recent years; discussion here focuses on illudinine.…”