N-Carbobenzoxyglycyl-prolyl-4-methylcoumarinyl amide → HCID 131726966, compound

HRID 748638Notes

Reaction equation

HRID 748638 reaction equation
[NH:1]([C:13](CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[CH3:28][C:29]([NH:31][CH:32]([C:39]([OH:41])=[O:40])[CH2:33][S:34][C:35]([NH:37][CH3:38])=[O:36])=[O:30].C1CN(C(CN)=O)[C@H](C(O)=O)C1.CC(NC(C(O)=O)CSC(NC)=O)=O.N(C(OCC1C=CC=CC=1)=O)CC(N1CCC[C@H]1C(NC1C=C2C(C(C)=CC(=O)O2)=CC=1)=O)=O.C1CN(C(CN)=O)[C@H](C(NC2C=CC3C(C(F)(F)F)=CC(OC=3C=2)=O)=O)C1>>[NH:1]([CH:13]=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[CH3:28][C:29]([NH:31][CH:32]([C:39]([OH:41])=[O:40])[CH2:33][S:34][C:35]([NH:37][CH3:38])=[O:36])=[O:30]

Participants

5

Reactant 4

HCID 125702N-Carbobenzoxyglycyl-prolyl-4-methylcoumarinyl amideHCID 25108518HCID 25108518, compoundHCID 131726968HCID 131726968, compoundHCID 131726970HCID 131726970, compound2×

Product 1

HCID 131726966HCID 131726966, compound

Procedure

To examine whether FAP could cleave other N-substituted-Gly-Pro-based substrates, N-methyl-, formyl-, succinyl-, benzyloxycarbonyl-(Z-) and biotinyl-Gly-Pro-AMCC substrates 6 were synthesized and reacted with FAP (37 nM) and DPP-4 (6.8 nM). With the exception of succinyl-Gly-Pro-AMCC, FAP cleaved all N-substituted-Gly-Pro-AMCC substrates 6 at rates 35-150% of the normalized rate for Gly-Pro-AMCC hydrolysis (Table 2), indicating that the protease tolerates other N-terminal blocking groups. Kinetic analysis with commercially available Z-Gly-Pro-AMC (Table 5) showed a catalytic efficiency about 3-fold lower than that for Gly-Pro-AFC (Table 4), consistent with these results. In contrast with FAP, DPP-4 cleaved only N-methyl-Gly-Pro-AMCC at a rate comparable to Gly-Pro-AMCC. A low rate of hydrolysis was obtained with formyl-Gly-Pro-AMCC substrates but no cleavage of succinyl-, Z-, or biotinyl-Gly-Pro-AMCC substrates was observed at concentrations up to 1 mM, indicating that DPP-4 does not tolerate N-acyl-Gly-Pro-based substrates. DPP-4 also showed little activity against commercially available Z-Gly-Pro-AMC (Table 5).

Workup

  1. customwere synthesized
  2. customreacted with FAP (37 nM) and DPP-4 (6.8 nM)
  3. customA low rate of hydrolysis

Sources & evidence

ORD record
ord-5e11439d426c4060b9b5b961300467bc
Source dataset
uspto-grants-2008_07
Patent number
US07399869B2

Reaction notes

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