Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Activity
2.2.1. Anticancer Evaluation
2.2.2. The Effect of the GA Peptides against the Normal Skin Fibroblasts Cell Line BJ-1
2.2.3. The Effect of the GA Peptide 5 on Bax, Bcl-2, and p53 Levels
2.2.4. Effect of the Peptide 5 on the Level of Caspase-3, Caspase-7, Tubulin Polymerization (TubB), and % of DNA Fragmentation
2.2.5. Antimicrobial Activity
2.3. Molecular Docking Study on Caspase-3 and Bcl-2
3. Materials and Methods
3.1. Chemistry
3.1.1. Synthesis of Amino Acid Ester Hydrochlorides and Boc-Protected Amino Acids
3.1.2. Synthesis of OH-GA-Gly-Gly-OEt; Ethyl 2-(2-(10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxamido)acetamido)acetate, (1)
3.1.3. Synthesis of Boc-l-Leu-N-Val-GA-GLy-Gly-Oet; 11-(2-(2-Ethoxy-2-oxoethylamino)-2-oxoethylcarbamoyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicen-3-yl 2-(2-(tert-Butoxycarbonylamino)-4-methylpentanamido)pentanoate, (2)
3.1.4. Synthesis of OH-GA-Gly-Gly-COOH; 2-(2-(10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxamido)acetamido)acetic acid; (3)
3.1.5. Synthesis of OH-GA-Gly-Gly- Gly-Gly-OEt; Ethyl 1-(10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicen-2-yl)-1,4,7,10-tetraoxo-2,5,8,11-tetraazatridecan-13-oate; (4)
3.1.6. Synthesis of OH-GA-Gly-Gly-Gly-Gly–COOH; 1-(10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicen-2-yl)-1,4,7,10-tetraoxo-2,5,8,11-tetraazatridecan-13-oic Acid; (5)
3.1.7. Synthesis of OH-GLA-GLy-Gly-l-Leu-Ome(Sh-12);Methyl 2-(2-(2-(10-Hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxamido)acetamido)acetamido)-4-methylpentanoate; (6)
3.1.8. Synthesis of OH-GA-Gly-Gly-l-Leu-COOH; 2-(2-(2-(10-Hydroxy-2, 4a, 6a, 6b, 9, 9, 12a-heptamethyl-13-oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14b-icosahydropicene-2-carboxamido) acetamido) acetamido)-4-methylpentanoic Acid; (7)
3.1.9. Synthesis of Boc-Gly-Gly-GA-Gly-Gly-l-Leu-Ome; Methyl 2-(2-(2-(10-(2-(2-(Tert-butoxycarbonylamino)acetamido)acetoxy)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxamido)acetamido)acetamido)-4-methylpentanoate, (8)
3.2. Biological Activities
3.2.1. Cytotoxicity
3.2.2. Estimation of Bcl-2 Level
3.2.3. Estimation of Bax Level
3.2.4. Estimation of Human p53 Level
3.2.5. Calculation of IC50Values
3.2.6. Human CASP-3(Caspase-3) Estimation
3.2.7. Human CASP-7 (Caspase-7) Estimation
3.2.8. Enzyme-Linked Immunosorbent Assay Kit for Tubulin Beta (TUBb)
3.2.9. Estimation of DNA Fragmentation through DPA Assay
3.2.10. In Vitro Antimicrobial Activity
3.3. Molecular Docking Study
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Compd. No. | IC50 (µg/mL) ± SD | ||
---|---|---|---|
MCF-7 | HCT-116 | HepG-2 | |
2 | 7.70 ± 1.3 | 70.30 ± 0.9 | --- |
3 | 5.1 ± 0.7 | 7.40 ± 0.4 | --- |
4 | 6.10 ± 0.4 | 73.0 ± 1.4 | --- |
5 | 5.0 ± 0.3 | 5.2 ± 0.8 | --- |
7 | 3.70 ± 0.2 | 3.0 ± 1.1 | 3.30 ± 0.1 |
8 | 6.90 ± 1.1 | 60.70 ± 0.6 | --- |
DOX | 7.07 ± 1 | 1.09 ± 3 | 0.54 ± 1 |
Pathogenic Microbial Strains | Diameter of Inhibition Zone (mm) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5 | 7 | 8 | GM | KC | ||
Gram-positive bacteria | Streptococcus pneumonia RCMB 010010 | 15 ± 0.16 | 12 ± 0.82 | 17 ± 0.21 | 11 ± 0.24 | 16 ± 0.12 | - | 12 ± 0.22 | 27.2 ± 0.80 | |
Staphylococcus aureus ATCC25923 | 15 ± 0.16 | 17 ± 0.11 | 17 ± 0.32 | 10 ± 0.13 | 15 ± 0.15 | - | 13 ± 0.24 | 25.4 ± 0.18 | ||
Micrococcus Luteus | 30 ± 0.21 | 30 ± 0.13 | 30 ± 0.25 | 29 ± 0.13 | 30 ± 0.15 | 30 ± 0.11 | 30 ± 0.17 | 24.4 ± 0.72 | ||
Gram-negative bacteria | Escherichia coli ATCC25922 | 20 ± 0.25 | 18 ± 0.14 | 16 ± 0.31 | 13 ± 0.15 | 18 ± 0.23 | 15 ± 0.21 | 15 ± 0.16 | 26.3 ± 0.15 | |
Pseudomonas aeruginosa ATCC7853 | 18 ± 0.15 | 15 ± 0.25 | 15 ± 0.18 | 13 ± 0.16 | 17 ± 0.16 | 13 ± 0.14 | 14 ± 0.16 | 24.41 ± 0.18 | ||
Proteus vulgaris RCMB 010085 | - | - | 17 ± 0.17 | 12 ± 0.23 | 10 ± 0.17 | 12 ± 0.14 | - | 20.0 ± 0.30 | ||
Yeast | Candida albicans | - | - | 12 ± 0.23 | 15 ± 0.12 | 13 ± 0.17 | - | - | 22.8 ± 0.10 |
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Moustafa, G.O.; Shalaby, A.; Naglah, A.M.; Mounier, M.M.; El-Sayed, H.; Anwar, M.M.; Nossier, E.S. Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives. Molecules 2021, 26, 4573. https://doi.org/10.3390/molecules26154573
Moustafa GO, Shalaby A, Naglah AM, Mounier MM, El-Sayed H, Anwar MM, Nossier ES. Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives. Molecules. 2021; 26(15):4573. https://doi.org/10.3390/molecules26154573
Chicago/Turabian StyleMoustafa, Gaber O., Ahmed Shalaby, Ahmed M. Naglah, Marwa M. Mounier, Heba El-Sayed, Manal M. Anwar, and Eman S. Nossier. 2021. "Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives" Molecules 26, no. 15: 4573. https://doi.org/10.3390/molecules26154573