Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates
Abstract
:1. Introduction
2. Material and Methods
2.1. Synthesis of cHP Isomers
2.2. Experimental Design and Treatments
2.3. Determination of Cellular Viability
2.4. Determination of AChE, TACE, and BACE1 Activities
2.5. Determination of TAC and TOS Levels
2.6. Determination of Apoptosis and Necrosis by Fluorescence Microscopy and Flow Cytometry
2.7. Determination of the Molecular Genetic Basis of Neuroprotection by cHP1-4
2.8. Determination of Cytotoxic and Genotoxic Potentials of cHP1-4
2.9. Statistical Analysis
3. Results
3.1. cHP Isomers Provided a Different Degree of Neuroprotection against Aβ1-42 Induced Cell Death in In Vitro AD Model
3.2. The Applications with cHP Isomers Altered the Activity of AChE but not the Activity of TACE and BACE1
3.3. cHP1-4 Supported Total Antioxidant Capacity without Altering Total Oxidative Status Levels in the Cellular AD Model
3.4. cHP4 Provided In Vitro Protection to Neuron-Like Cells against Apoptotic and Necrotic Effects by Aβ1-42 in Cellular AD Model
3.5. cHP4 Modulated the Alterations of Gene Expressions by Aβ1-42 Exposure
3.6. cHP4 Exhibited Noncytotoxic and Non-Genotoxic Features in Cultured Human Whole Blood Cells
4. Discussion
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
References
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Groups | % Cell Viability (MTT Assay) | % Cell Viability (LDH Assay) |
---|---|---|
Control (−) | 100 e | 100 g |
20 µM Aβ1-42 | 50.8 ± 3.7 a | 48.9 ± 2.5 a |
Aβ + 0.1 µM cHP1 | 50.9 ± 3.2 a | 48.7 ± 2.7 a |
Aβ + 1 µM cHP1 | 51.3 ± 4.0 a | 49.5 ± 3.0 a |
Aβ + 10 µM cHP1 | 52.5 ± 3.7 a | 50.9 ± 2.5 a |
Aβ + 25 µM cHP1 | 56.2 ± 4.4 ab | 53.6 ± 2.4 ab |
Aβ + 50 µM cHP1 | 56.8 ± 3.5 ab | 57.1 ± 2.8 b |
Aβ + 100 µM cHP1 | 57.9 ± 4.1 ab | 58.8 ± 3.0 b |
Aβ + 0.1 µM cHP2 | 51.5 ± 3.3 a | 49.9 ± 2.8 a |
Aβ + 1 µM cHP2 | 52.7 ± 4.2 a | 50.6 ± 3.1 a |
Aβ + 10 µM cHP2 | 55.8 ± 5.0 ab | 52.9 ± 2.7 a |
Aβ + 25 µM cHP2 | 57.1 ± 4.8 ab | 53.1 ± 2.8 ab |
Aβ + 50 µM cHP2 | 56.9 ± 4.1 ab | 58.7 ± 2.4 b |
Aβ + 100 µM cHP2 | 59.7 ± 3.8 b | 60.1 ± 3.3 b |
Aβ + 0.1 µM cHP3 | 51.7 ± 4.1 a | 53.5 ± 3.0 ab |
Aβ + 1 µM cHP3 | 55.5 ± 4.3 ab | 58.9 ± 2.5 b |
Aβ + 10 µM cHP3 | 59.6 ± 4.7 b | 63.6 ± 2.8 bc |
Aβ + 25 µM cHP3 | 66.5 ± 4.6 b | 66.8 ± 3.0 c |
Aβ + 50 µM cHP3 | 69.0 ± 5.0 b | 72.4 ± 3.3 d |
Aβ + 100 µM cHP3 | 71.3 ± 6.6 bc | 77.3 ± 3.5 de |
Aβ + 0.1 µM cHP4 | 52.8 ± 3.6 a | 52.4 ± 2.7 ab |
Aβ + 1 µM cHP4 | 55.9 ± 4.7 ab | 56.8 ± 2.9 b |
Aβ + 10 µM cHP4 | 63.9 ± 5.2 b | 67.0 ± 3.4 c |
Aβ + 25 µM cHP4 | 71.2 ± 6.8 bc | 74.6 ± 3.2 d |
Aβ + 50 µM cHP4 | 79.4 ± 6.2 c | 82.3 ± 3.5 e |
Aβ + 100 µM cHP4 | 87.9 ± 6.6 d | 88.5 ± 3.6 f |
Groups | TAC Level (mmolTrolox Equiv./L) | TOS Level (µmol H2O2 Equiv./L) |
---|---|---|
Control (−) | 4.8 ± 0.7 b | 2.1 ± 0.3 a |
Control (+) | 12.7 ± 1.3 f | 5.7 ± 0.6 c |
20 µM Aβ1-42 | 2.6 ± 0.4 a | 5.1 ± 0.5 b |
0.1 µM cHP1 | 4.9 ± 0.6 b | 2.0 ± 0.3 a |
1 µM cHP1 | 5.2 ± 0.8 b | 1.8 ± 0.2 a |
10 µM cHP1 | 5.6 ± 0.7 c | 2.0 ± 0.3 a |
25 µM cHP1 | 6.1 ± 0.6 c | 2.3 ± 0.4 a |
50 µM cHP1 | 6.3 ± 0.5 c | 2.2 ± 0.2 a |
100 µM cHP1 | 6.5 ± 0.7 c | 2.0 ± 0.2 a |
0.1 µM cHP2 | 4.7 ± 0.5 b | 1.7 ± 0.1 a |
1 µM cHP2 | 4.9 ± 0.7 b | 2.0 ± 0.2 a |
10 µM cHP2 | 5.3 ± 0.6 b | 2.1 ± 0.2 a |
25 µM cHP2 | 5.4 ± 0.8 b | 2.3 ± 0.3 a |
50 µM cHP2 | 6.1 ± 0.6 c | 2.3 ± 0.4 a |
100 µM cHP2 | 6.4 ± 0.7 c | 2.4 ± 0.3 a |
0.1 µM cHP3 | 5.0 ± 0.3 b | 1.9 ± 0.2 a |
1 µM cHP3 | 5.3 ± 0.5 c | 2.0 ± 0.2 a |
10 µM cHP3 | 5.8 ± 0.4 c | 2.0 ± 0.2 a |
25 µM cHP3 | 6.7 ± 0.5 c | 2.2 ± 0.3 a |
50 µM cHP3 | 7.1 ± 0.8 d | 2.2 ± 0.3 a |
100 µM cHP3 | 7.6 ± 0.5 d | 2.4 ± 0.2 a |
0.1 µM cHP4 | 4.9 ± 0.7 b | 1.8 ± 0.1 a |
1 µM cHP4 | 5.5 ± 0.7b | 2.0 ± 0.3 a |
10 µM cHP4 | 6.4 ± 0.6 c | 2.0 ± 0.2 a |
25 µM cHP4 | 6.8 ± 0.4 c | 2.0 ± 0.2 a |
50 µM cHP4 | 7.7 ± 0.7 d | 1.9 ± 0.1 a |
100 µM cHP4 | 8.9 ± 0.9 e | 2.0 ± 0.2 a |
Groups | TAC Level (mmolTrolox Equiv./L) | TOS Level (µmol H2O2 Equiv./L) | |
---|---|---|---|
Control (−) | 4.8 ± 0.7 d | 2.1 ± 0.3 a | |
Control (+) | 12.7 ± 1.3 e | 5.7 ± 0.6 e | |
20 µM Aβ1-42 | 2.6 ± 0.4 a | 5.1 ± 0.5 d | |
Aβ1-42 plus cHP1 | 0.1 µM | 2.5 ± 0.5 a | 5.0 ± 0.7 d |
1 µM | 2.6 ± 0.4 a | 4.8 ± 0.5 d | |
10 µM | 2.7 ± 0.6 a | 4.7 ± 0.5 d | |
25 µM | 2.8 ± 0.5 a | 4.4 ± 0.6 d | |
50 µM | 3.0 ± 0.7 ab | 4.0 ± 0.5 c | |
100 µM | 3.2 ± 0.8 ab | 3.9 ± 0.4 c | |
Aβ1-42 plus cHP2 | 0.1 µM | 2.7 ± 0.5 a | 4.8 ± 0.6 d |
1 µM | 2.8 ± 0.5 a | 4.7 ± 0.7 d | |
10 µM | 2.8 ± 0.5 a | 4.5 ± 0.5 d | |
25 µM | 3.0 ± 0.7 ab | 4.4 ± 0.4 d | |
50 µM | 3.1 ± 0.7 ab | 4.3 ± 0.6 d | |
100 µM | 3.2 ± 0.8 ab | 4.0 ± 0.4 c | |
Aβ1-42 plus cHP3 | 0.1 µM | 2.7 ± 0.6 a | 4.7 ± 0.3 d |
1 µM | 2.9 ± 0.5 a | 4.6 ± 0.4 d | |
10 µM | 3.1 ± 0.7 ab | 4.5 ± 0.5 d | |
25 µM | 3.4 ± 0.7 b | 4.2 ± 0.4 d | |
50 µM | 3.5 ± 0.6 b | 3.9 ± 0.6 c | |
100 µM | 3.8 ± 0.8 c | 3.6 ± 0.5 c | |
Aβ1-42 plus cHP4 | 0.1 µM | 2.7 ± 0.6 a | 4.6 ± 0.7 d |
1 µM | 2.9 ± 0.5 a | 4.3 ± 0.6 d | |
10 µM | 3.5 ± 0.7 b | 4.0 ± 0.5 c | |
25 µM | 3.7 ± 0.6 b | 3.6 ± 0.4 c | |
50 µM | 3.9 ± 0.8 c | 3.0 ± 0.4 b | |
100 µM | 4.6 ± 1.0 d | 2.7 ± 0.3 b |
Gene | Aβ1-42 | Aβ1-42 plus CHP4 |
---|---|---|
ACADVL | −0.77 | 3.83 |
AKT1 | 0.15 | 0.08 |
ADM2 | −0.43 | 3.68 |
BCL2 | −0.94 | 4.67 |
BCL2L1 | −0.77 | 5.12 |
CASP8 | 3.45 | 2.89 |
CASP9 | 2.91 | 0.83 |
CYP2D6 | −0.45 | 1.75 |
DNAJB9 | −0.63 | 2.35 |
ERCC1 | 10.25 | 2.55 |
FASLG | 1.14 | 0.64 |
HSPA1A | 3.66 | 0.16 |
METAP2 | −0.71 | 3.13 |
PARP2 | 7.93 | 2.06 |
SLC7A11 | −0.38 | 13.14 |
UHRF1 | −0.54 | 3.12 |
Groups | SCEs/Cell | MN/2000 Cells | Nuclear Division Index (NDI) | |
---|---|---|---|---|
Control (-) | 4.6 ± 0.7 a | 0.8 ± 0.1 a | 1.5 ± 0.3 b | |
Control (+) | 11.4 ± 0.9 b | 3.9 ± 0.5 b | 1.0 ± 0.2 a | |
cHP4 | 0.1 µM | 4.3 ± 0.4 a | 0.7 ± 0.2 a | 1.4 ± 0.2 b |
1 µM | 4.1 ± 0.7 a | 0.8 ± 0.2 a | 1.4 ± 0.1 b | |
10 µM | 4.5 ± 0.5 a | 0.9 ± 0.2 a | 1.4 ± 0.2 b | |
25 µM | 4.3 ± 0.7 a | 0.8 ± 0.2 a | 1.4 ± 0.3 b | |
50 µM | 4.7 ± 0.6 a | 0.9 ± 0.2 a | 1.3 ± 0.2 b | |
100 µM | 4.6 ± 0.5 a | 0.8 ± 0.2 a | 1.3 ± 0.2 b |
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Turkez, H.; Cacciatore, I.; Arslan, M.E.; Fornasari, E.; Marinelli, L.; Di Stefano, A.; Mardinoglu, A. Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates. Biomolecules 2020, 10, 737. https://doi.org/10.3390/biom10050737
Turkez H, Cacciatore I, Arslan ME, Fornasari E, Marinelli L, Di Stefano A, Mardinoglu A. Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates. Biomolecules. 2020; 10(5):737. https://doi.org/10.3390/biom10050737
Chicago/Turabian StyleTurkez, Hasan, Ivana Cacciatore, Mehmet Enes Arslan, Erika Fornasari, Lisa Marinelli, Antonio Di Stefano, and Adil Mardinoglu. 2020. "Histidyl-Proline Diketopiperazine Isomers as Multipotent Anti-Alzheimer Drug Candidates" Biomolecules 10, no. 5: 737. https://doi.org/10.3390/biom10050737