Synthesis of Arginase Inhibitors: An Overview
Abstract
:1. Introduction
2. First-Generation Inhibitors
2.1. α-Amino Acid Derivatives
2.2. Boronic Acid Derivatives
3. Second-Generation Inhibitors
3.1. Basic Side Chain α-Substituted ABH Analogues
3.2. Non-Basic Side Chain α-Substituted ABH Analogues
4. Third-Generation Inhibitors
5. Fourth-Generation Inhibitors
5.1. Peptide Boronic Acid Derivatives
5.1.1. Peptide Cyclic Inhibitors
5.1.2. Proline Cyclic Inhibitors
6. Side Chain β-Substituted ABH Analogues
7. Natural Compounds as ARG Inhibitors
7.1. Polyphenols
7.2. Cinnamide Derivatives
8. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Compound | R | IC50 |
---|---|---|
21 (S)-2-amino-6-borono-2-(1S,3R)-3-(3-phenylpropylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) | |
22 (S)-2-amino-6-borono-2-((1S,3R)-3-(3-(3-chloro-5fluorophenyl)propylamino) cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 0.1–25 nM (hARG-2) | |
23 (S)-2-amino-6-borono-2-((1s,3R)-3-(3-(3,4-difluorophenyl)propylamino)cyclobutyl) hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
24 (S)-2-amino-6-borono-2-((1S,3R)-3-(3-(2,4-dichlorophenyl)propylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
25 (S)-2-amino-6-borono-2-((1S,3R)-3-(2,3-dihydro-1h-inden-2yl-amino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) | |
26 (S)-2-amino-6-borono-2-((1S,3R)-3-(4-tert-butylbenzylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
27 (S)-2-amino-2-((1S,3R)-3-(biphenyl-3-ylmethylamino)cyclobutyl)-6-boronohexanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) | |
28 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-(trifluoromethyl)biphenyl-3-yl) methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
29 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-chlorobiphenyl-3yl)methylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
30 (S)-2-amino-6-borono-2-((1S,3R)-3-((4-fluoronaphthalen-1yl)methylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
31 (S)-2-amino-6-borono-2-((1S,3R)-3-((5-fluoronaphthalen-1yl)methylaminocyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) | |
32 (S)-2-amino-2-(1S,3R)-3-(anthracen-9-ylmethylamino)cyclobutyl)-6-borono hexanoic acid | 26–100 nM (hARG-1) 0.1–25 nM (hARG-2) | |
33 (S)-2-amino-6-borono-2-((1S,3R)-3-(2-morpholinobenzylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
34 (S)-2-amino-6-borono-2-((1R,3R)-3-(((S)-1,2,3,4-tetrahydroisoquinolin-3-yl)methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
35 (S)-2-amino-6-borono-2-((1S,3R)-3-((2,3-dihydrobenzofuran-5-yl)methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
36 (S)-2-amino-6-borono-2-((1S,3R)-3-((3′,4′-dichlorobiphenyl-4yl)methylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
37 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-chlorobiphenyl-4yl)methylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
38 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-(trifluoromethyl)biphenyl-4-yl)methylamino)cyclobutyl) hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
39 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-fluorobiphenyl-4yl)methylamino)cyclobutyl)hecanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) | |
40 (S)-2-amino-6-borono-2-((1S,3R)-3-(4-hydroxybenzylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
41 (S)-2-amino-6-borono-2-((1S,3R)-3-(4-(4-chlorophenoxy)benzylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
42 (S)-2-amino-6-borono-2-(1S,3R)-3-((4′-chlorobiphenyl-2-yl)methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
43 (S)-2-amino-6-borono-2-((1S,3R)-3-((6-phenylpyridin-3-yl)methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 0.1–25 nM (hARG-2) | |
44 (S)-2-((1S,3R)-3-((9h-fluoren-2-yl)methylamino)cyclobutyl)-2-amino-6-borono-hexanoic acid | 0.1–25 nM (hARG-1) 0.1–25 nM (hARG-2) | |
45 (S)-2-amino-6-borono-2-((1S,3R)-3-((4′-(trifluoromethyl)biphenyl-2 yl)methylamino)cyclobutyl)hexanoic acid | 26–100 nM (hARG-1) 26–100 nM (hARG-2) | |
46 (S)-2-amino-6-borono-2-((1S,3R)-3-(4-cyclohexylbenzylamino)cyclobutyl)hexanoic acid | 0.1–25 nM (hARG-1) 26–100 nM (hARG-2) |
Compound | Structure | ARG-1 Activity | ARG-2 Activity |
---|---|---|---|
91 Chlorogenic acid | IC50 = 10.6 µM a | ||
92 Picetannol | IC50 = 12.1 µM a | ||
93 Resveratrol | IC50 = 18.2 µM a | ||
94 Taxifolin | IC50 = 23.2 µM a | ||
95 Piceatannol-3′-O-β-D-glucopyranoside | IC50 = 11.22 µM b | IC50 = 11.06 µM c | |
96 Ellagic acid | IC50 = 78.9 µM a | ||
97 Luteolin-7-diglucoside | IC50 = 152.4 µM a | ||
98 Luteolin-7-glucoside | IC50 = 99.4 µM a | ||
99 Luteolin | IC50 = 95.3 µM a | ||
100 Scirpusin B | IC50 = 22.6 µM a | ||
101 ε-Viniferin | IC50 = 27.8 µM a | ||
102 Cyperusphenol B | IC50 = 12.2 µM a | ||
103 Carexinol A | IC50 = 25.3 µM a | ||
104 Virgatanol | IC50 = 182.1 µM a | ||
105 Sauchinone | IC50 = 61.4 µM d | ||
106 (2S)-5,7-dihydroxy-8,20-dimethoxyflavanone | IC50 = 25.1 µM c | ||
107 (2S)-5,20,50-trihydroxy-7, 8-dimethoxyflavanone | IC50 = 11.6 µM c | ||
108 Caffeic acid phenylamide (CAPA) | IC50 = 6.9 µM a IC50 = 60.3 µM e |
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Molaro, M.C.; Battisegola, C.; Schiano, M.E.; Failla, M.; Rimoli, M.G.; Lazzarato, L.; Chegaev, K.; Sodano, F. Synthesis of Arginase Inhibitors: An Overview. Pharmaceutics 2025, 17, 117. https://doi.org/10.3390/pharmaceutics17010117
Molaro MC, Battisegola C, Schiano ME, Failla M, Rimoli MG, Lazzarato L, Chegaev K, Sodano F. Synthesis of Arginase Inhibitors: An Overview. Pharmaceutics. 2025; 17(1):117. https://doi.org/10.3390/pharmaceutics17010117
Chicago/Turabian StyleMolaro, Maria Cristina, Chiara Battisegola, Marica Erminia Schiano, Mariacristina Failla, Maria Grazia Rimoli, Loretta Lazzarato, Konstantin Chegaev, and Federica Sodano. 2025. "Synthesis of Arginase Inhibitors: An Overview" Pharmaceutics 17, no. 1: 117. https://doi.org/10.3390/pharmaceutics17010117
APA StyleMolaro, M. C., Battisegola, C., Schiano, M. E., Failla, M., Rimoli, M. G., Lazzarato, L., Chegaev, K., & Sodano, F. (2025). Synthesis of Arginase Inhibitors: An Overview. Pharmaceutics, 17(1), 117. https://doi.org/10.3390/pharmaceutics17010117