Phosphinotripeptidic Inhibitors of Leucylaminopeptidases
Abstract
:1. Introduction
2. Results and Discussions
2.1. Chemistry
2.2. Enzyme Inhibition
2.3. Molecular Docking
3. Materials and Methods
3.1. Chemistry
3.1.1. [1-(N-Benzyloxycarbonylamino)-3-phenylpropyl]phosphinic Acid (12)
3.1.2. [1-(N-Benzyloxycarbonylamino)-3-methylbutyl]phosphinic Acid (13)
3.1.3. General Procedure for the Synthesis of 14 and 15
Methyl 3-[1-N-(benzyloxycarbonylamino)-3-phenylpropyl]hydroxyphosphinyl propanoate (14)
Methyl 3-[1-N-(benzyloxycarbonylamino)-3-methylbutyl]hydroxyphosphinyl propanoate (15)
3.1.4. General Procedure for the Protection of Hydroxyphosphinyl Group in 14 and 15
Methyl 3-[(1-N-(benzyloxycarbonylamino)-3-phenylpropyl)adamantyloxyphoshinyl]propanoate (16)
Methyl 3-[(1-N-(benzyloxycarbonylamino)-3-methylbutyl)adamantyloxyphoshinyl]propanoate (17)
3.1.5. General Procedure for the Coupling Reaction of Building Blocks 16 and 17 Involving HOBt and EDC
Methyl 3-[(adamantan-1-yloxy)-(1-((S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butan-amido)-3-phenylpropyl)phosphinyl]propanoate (20)
Methyl 3-[(adamantan-1-yloxy)(1-((S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butan-amido)-3-methylbutyl)phosphinyl]propanoate (21)
Methyl 3-[(adamantan-1-yloxy)(1-((S)-2-(tert-butoxycarbonylamino)-4-((tert-butyldime-thylsilyl)-oxy)butanamido)-3-methylbutyl)phosphinyl]propanoate (22)
Methyl 3-[(adamantan-1-yloxy)(1-((S)-2-(tert-butoxycarbonylamino)-4-(hydroxybutan-amido)-3-methylbutyl)phosphinyl]propanoate (23)
Methyl 3-[(adamantan-1′-yloxy)-((1-((S)-3-([1,1′-biphenyl]-4-yl)-2-(tert-butoxycarbonyl-amino)propanamido)-3-phenylpropyl)phosphinyl]propanoate (26)
Methyl 3-[(adamantan-1-yloxy)-((1-((S)-3-([1,1′-biphenyl]-4-yl)-2-(tert-butoxycarbonyl-amino)propanamido)-3-methylbutyl)phosphinyl]propanoate (27)
Methyl 3-[(adamantan-1-yloxy)-((1-((S)-3-(4-benzoylphenyl)-2-(tert-butoxycarbonyl-amino)-propanamido)-3-phenylpropyl)phosphinyl]propanoate (28)
Methyl 3-[(adamantan-1-yloxy)-((1-((S)-3-(4-benzoylphenyl)-2-(tert-butoxycarbony)-amino)-propanamido)-3′-methylbutyl)phosphinyl]propanoate (29)
3.1.6. General Procedure for Removal of the C-Terminal Methyl Ester Group
3-[(Adamantan-1-yloxy)(1-((S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanamido)-3-phenylpropyl)phosphinyl]propanoic acid (24)
3-[(Adamantan-1-yloxy)(1-((S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butanamido)-3-methylbutyl)phosphinyl]propanoic acid (25)
3.1.7. General Procedure for Removal of Boc and Ad Protecting Groups
Methyl 3-[(1-((S)-2-amino-4-(methylthio)butanamido)-3-phenylpropyl)phosphinyl]propanoate (1)
Methyl 3-[(1-((S)-2-amino-4-(methylthio)butanamido)-3-methylbutyl)phosphinyl]propanoate (2)
Methyl 3-[(1-((S)-2-amino-4-(hydroxybutanamido)-3-methylbutyl)phosphinyl]propanoate (3)
3-[(1-((S)-2-Amino)-4-(methylthio)butanamido)-3-phenylpropyl)-phosphinyl]propanoic acid (4)
3-[(1-((S)-2-Amino-4-(methylthio)butanamido)-3-methylbutyl)phosphinyl]propanoic acid (5)
Methyl 3-[(1-((S)-3-([1,1′-biphenyl]-4-yl)-2-aminopropanamido)-3-phenylpropyl)phosphinyl]-propanoate (6)
Methyl 3-[(1-((S)-3-([1,1′-biphenyl]-4-yl)-2-aminopropanamido)-3-methylbutyl)phosphinyl]-propanoate (7)
Methyl 3-[(1-((S)-2-amino-3-(4-benzoylphenyl)propanamido)-3-phenylpropyl)phosphinyl]-propanoate (8)
Methyl 3-[(1-((S)-2-amino-3-(4-benzoylphenyl)propanamido)-3-methylbutyl)phosphinyl]-propanoate (9)
3.2. Inhibitor Activity
3.2.1. Enzyme Preparation
3.2.2. Kinetic Assays
3.2.3. Kinetic Calculation
3.3. Molecular Modeling
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Acknowledgments
Conflicts of Interest
References
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Entry | Structure | KI [μM] | ||
---|---|---|---|---|
SsLAP | HvLAP | |||
1 | Met-hPheP[CH2]Gly-OMe | | 532 ± 46 | 38 ± 9 |
2 | Met-LeuP[CH2]Gly-OMe | | 1090 ± 73 | 649 ± 43 |
3 | Ser-LeuP[CH2]Gly-OMe | | 14 ± 1 | 121 ± 19 |
4 | Met-hPheP[CH2]Gly | | 229 ± 40 | 228 ± 10 |
5 | Met-LeuP[CH2]Gly | | 3618 ± 433 | 1035 ± 102 |
6 | Bip-hPheP[CH2]Gly-OMe | | 175 ± 3 | 878 ± 70 |
7 | Bip-LeuP[CH2]Gly-OMe | | 130 ± 14 | 1303 ± 84 |
8 | Bpa-hPheP[CH2]Gly-OMe | | 95 ± 9 | 159 ± 25 |
9 | Bpa-LeuP[CH2]Gly-OMe | | 507 ± 31 | 797 ± 76 |
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Jewgiński, M.; Haremza, K.; de los Santos, J.M.; Es Sbai, Z.; Oszywa, B.; Pawełczak, M.; Palacios, F.; Latajka, R. Phosphinotripeptidic Inhibitors of Leucylaminopeptidases. Int. J. Mol. Sci. 2021, 22, 5090. https://doi.org/10.3390/ijms22105090
Jewgiński M, Haremza K, de los Santos JM, Es Sbai Z, Oszywa B, Pawełczak M, Palacios F, Latajka R. Phosphinotripeptidic Inhibitors of Leucylaminopeptidases. International Journal of Molecular Sciences. 2021; 22(10):5090. https://doi.org/10.3390/ijms22105090
Chicago/Turabian StyleJewgiński, Michał, Kinga Haremza, Jesús M. de los Santos, Zouhair Es Sbai, Bartosz Oszywa, Małgorzata Pawełczak, Francisco Palacios, and Rafał Latajka. 2021. "Phosphinotripeptidic Inhibitors of Leucylaminopeptidases" International Journal of Molecular Sciences 22, no. 10: 5090. https://doi.org/10.3390/ijms22105090