Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity
Abstract
:1. Introduction
2. Results
2.1. Compound Selection
2.2. Synthesis
2.3. In Silico Analysis
- 1 if Indki > mean (Indki), 0 otherwise;
- 1 if ΔEki < mean (ΔEki), 0 otherwise.
2.4. The OGTT in C57BL/6 Mice
2.5. The OGTT in AY Mice
2.6. A Biochemical Blood Assay in Treated AY Mice
2.7. Histological Examination
3. Discussion
- –
- For PPARD, the highest Ind value corresponds to the highest docking energy ΔE;
- –
- For FFAR1 also, the highest value of the Ind estimate corresponds to the highest docking energy ΔE;
- –
- For DPP4, the lowest value of the Ind estimate corresponds to the minimum docking energy ΔE.
4. Materials and Methods
4.1. Chemistry
4.1.1. General Procedure for Hydrolysis
4.1.2. 3-(4-((4-(((1R,2R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ylamino)methyl)- phenoxy)methyl)phenyl)propanoic acid hydrochloride 2
4.1.3. 3-(4-(4-(((1S,2R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yloxy)methyl)- benzyloxy)phenyl)propanoic acid 3
4.1.4. 3-(4-(4-(((1R,2S,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ylamino)methyl)- benzyloxy)phenyl)propanoic acid hydrochloride 4
4.1.5. Methyl 3-(4-(4-(((1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylamino)- methyl)phenethyl)phenyl)propanoate 7
4.1.6. Methyl 3-(4-(4-(((1S,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)methyl)- benzyloxy)phenyl)Propanoate 9
4.1.7. 4-(4-(Bromomethyl)benzyloxy)benzaldehyde 12
4.1.8. Diethyl 2-(4-((4-Formylphenoxy)methyl)benzyl)malonate 13
4.1.9. Ethyl 3-(4-((4-Formylphenoxy)methyl)phenyl)propanoate 14
4.1.10. Ethyl 3-(4-((4-(((1R,2R,4R)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-ylamino)methyl)- phenoxy)methyl)phenyl)propanoate 15
4.2. Biological Experiments
4.2.1. Animals
4.2.2. The OGTT
4.2.3. The Design of the Experiment on AY Mice
4.2.4. Biochemical Assays
4.2.5. Histological Examination
4.3. Computational Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Target Name 2 | Protein Symbol 3 | UniProt 4 | Ligand 5 |
---|---|---|---|
Cleavage of poly- and oligosaccharides | |||
Pancreatic alpha-amylase | AMY2A | P04746 | inhibitor |
Maltase-glucoamylase, intestinal | MGAM | O43451 | inhibitor |
Insulinogens | |||
Sulfonylurea receptor 1 | SUR1 | Q09428 | inhibitor |
Incretin mimetics | |||
Dipeptidyl peptidase 4 | DPP4 | P27487 | inhibitor |
Gastric inhibitory polypeptide receptor | GIPR | P48546 | agonist |
Glucagon-like peptide receptor 1 | GLP1R | P43220 | agonist |
Trace amine-associated receptor 1 | TAAR1 | Q96RJ0 | agonist |
Insulin resistance | |||
Free fatty acid receptor 1 (GPR40) | FFAR1 | O14842 | agonist |
Free fatty acid receptor 2 (GPR43) | FFAR2 | O15552 | agonist |
Free fatty acid receptor 3 (GPR41) | FFAR3 | O14843 | agonist |
Free fatty acid receptor 4 (GPR120) | FFAR4 | Q5NUL3 | agonist |
Peroxisome proliferator-activated receptor alpha | PPARA | Q07869 | agonist |
Peroxisome proliferator-activated receptor delta | PPARD | Q03181 | agonist |
Peroxisome proliferator-activated receptor gamma | PPARG | P37231 | agonist |
Protein-tyrosine phosphatase 1B (PTP1B) | PTPN1 | P18031 | inhibitor |
Gluconeogenesis and glycogenolysis | |||
Glycogen phosphorylase, liver form | PYGL | P06737 | inhibitor |
Glycogen phosphorylase, muscle form | PYGM | P11217 | inhibitor |
Glucagon | GCG | P01275 | inhibitor |
Glucagon receptor | GCGR | P47871 | inhibitor |
Phosphoenolpyruvate carboxykinase, cytosolic | PCK1 | P35558 | inhibitor |
Fructose-1,6-bisphosphatase 1 | FBP1 | P09467 | inhibitor |
Glycolysis and glycogen synthesis | |||
Pyruvate dehydrogenase kinase 4 | PDK4 | Q16654 | activator |
6-phosphofructokinase, muscle type | PFKM | P08237 | activator |
Glucose transport | |||
Sodium/glucose cotransporter 2 | SGLT2 | P31639 | inhibitor |
Target Name | Protein Symbol | IndMean 1 | TMean 2 |
---|---|---|---|
Peroxisome proliferator-activated receptor delta | PPARD | 2.93 | 0.624 |
Free fatty acid receptor 1 (GPR40) | FFAR1 | 1.87 | 0.684 |
Dipeptidyl peptidase 4 | DPP4 | 1.86 | 0.478 |
Glycogen phosphorylase, liver form | PYGL | 1.70 | 0.460 |
Protein-tyrosine phosphatase 1B (PTP1B) | PTPN1 | 1.59 | 0.418 |
Free fatty acid receptor 4 (GPR120) | FFAR4 | 1.58 | 0.651 |
Pancreatic alpha-amylase | AMY2A | 1.57 | 0.195 |
6-phosphofructokinase, muscle type | PFKM | 1.00 | 0.230 |
Gastric inhibitory polypeptide receptor | GIPR | 0.35 | 0.426 |
Peroxisome proliferator-activated receptor alpha | PPARA | 0.33 | 0.627 |
Glucagon-like peptide receptor 1 | GLP1R | 0.00 | 0.181 |
Pyruvate dehydrogenase kinase 4 | PDK4 | 0.00 | 0.145 |
Trace amine-associated receptor 1 | TAAR1 | −0.18 | 0.441 |
Maltase-glucoamylase, intestinal | MGAM | −0.25 | 0.118 |
Peroxisome proliferator-activated receptor gamma | PPARG | −0.28 | 0.586 |
Glycogen phosphorylase, muscle form | PYGM | −0.33 | 0.381 |
Sulfonylurea receptor 1 | SUR1 | −0.50 | 0.479 |
Free fatty acid receptor 3 (GPR41) | FFAR3 | −0.75 | 0.194 |
Glucagon receptor | GCGR | −0.76 | 0.430 |
Sodium/glucose cotransporter 2 | SGLT2 | −1.31 | 0.491 |
Fructose-1,6-bisphosphatase 1 | FBP1 | −1.45 | 0.384 |
Free fatty acid receptor 2 (GPR43) | FFAR2 | −1.45 | 0.459 |
Glucagon | GCG | −1.65 | 0.486 |
Phosphoenolpyruvate carboxykinase, cytosolic | PCK1 | −2.50 | 0.228 |
Target Name | 1 | 2 | 3 | 4 |
---|---|---|---|---|
Peroxisome proliferator-activated receptor delta | 2.70 | 2.50 | 3.80 | 2.70 |
Free fatty acid receptor 1 (GPR40) | 1.40 | 1.60 | 3.08 | 1.40 |
Dipeptidyl peptidase 4 | 2.00 | 2.54 | 0.89 | 2.00 |
Glycogen phosphorylase, liver form | 1.70 | 1.70 | 1.70 | 1.70 |
Protein-tyrosine phosphatase 1B (PTP1B) | 1.79 | 1.71 | 1.08 | 1.79 |
Free fatty acid receptor 4 (GPR120) | 1.70 | 1.90 | 1.00 | 1.70 |
Pancreatic alpha-amylase | 1.40 | 1.90 | 1.58 | 1.40 |
6-phosphofructokinase, muscle type | 1.00 | 1.00 | 1.00 | 1.00 |
Gastric inhibitory polypeptide receptor | 0.32 | 0.51 | 0.27 | 0.32 |
Peroxisome proliferator-activated receptor alpha | 0.20 | −1.10 | 2.00 | 0.20 |
Glucagon-like peptide receptor 1 | 0.00 | 0.00 | 0.00 | 0.00 |
Pyruvate dehydrogenase kinase 4 | 0.00 | 0.00 | 0.00 | 0.00 |
Trace amine-associated receptor 1 | −0.90 | −1.10 | 2.20 | −0.90 |
Maltase-glucoamylase, intestinal | −0.20 | −0.20 | −0.40 | −0.20 |
Peroxisome proliferator-activated receptor gamma | −0.90 | −0.90 | 1.60 | −0.90 |
Glycogen phosphorylase, muscle form | −1.10 | −0.80 | 1.70 | −1.10 |
Sulfonylurea receptor 1 | −0.50 | −0.50 | −0.50 | −0.50 |
Free fatty acid receptor 3 (GPR41) | −0.75 | −0.75 | −0.75 | −0.75 |
Glucagon receptor | −0.83 | −0.66 | −0.70 | −0.83 |
Sodium/glucose cotransporter 2 | −1.90 | −2.10 | 0.65 | −1.90 |
Fructose-1,6-bisphosphatase 1 | −1.60 | −0.70 | −1.90 | −1.60 |
Free fatty acid receptor 2 (GPR43) | −2.70 | −2.20 | 1.80 | −2.70 |
Glucagon | −1.73 | −1.73 | −1.40 | −1.73 |
Phosphoenolpyruvate carboxykinase, cytosolic | −2.50 | −2.50 | −2.50 | −2.50 |
Total sum of indices of activity levels | −1.40 | 0.12 | 16.21 | −1.40 |
Sum of significant indices of activity levels | 14.21 | 15.36 | 24.36 | 14.21 |
Target | Compound | Ind 1 | ΔE 2 | BinInd 4 | BinΔE 5 |
---|---|---|---|---|---|
Peroxisome proliferator- activated receptor delta | 1 | 2.70 | −9.30 | 0 | 0 |
2 | 2.50 | −9.40 | 0 | 0 | |
3 | 3.80 | −9.80 | 1 | 1 | |
4 | 2.70 | −9.70 | 0 | 1 | |
Mean 3 | 2.93 | −9.55 | |||
Free fatty acid receptor 1 (GPR40) | 1 | 1.40 | −10.00 | 0 | 0 |
2 | 1.60 | −9.80 | 0 | 0 | |
3 | 3.08 | −10.20 | 1 | 1 | |
4 | 1.40 | −10.10 | 0 | 1 | |
Mean | 1.87 | −10.03 | |||
Dipeptidyl peptidase 4 | 1 | 2.00 | −9.10 | 1 | 1 |
2 | 2.54 | −9.10 | 1 | 1 | |
3 | 0.89 | −8.80 | 0 | 0 | |
4 | 2.00 | −9.10 | 1 | 1 | |
Mean | 1.86 | −9.03 | |||
Spearman test RSp | 0.7143 | ||||
p | 9.06 × 10−3 |
Group | TC, mmol/L | TGs, mmol/L | HDL-C, mg/dL | LDL-C, mg/dL | Glu, mmol/L |
---|---|---|---|---|---|
C57BL/6 mice | 1.59 ± 0.14 | 0.54 ± 0.04 | 82.66 ± 5.29 | 15.13 ± 2.02 | 5.55 ± 0.38 |
AY mice | 2.59 ± 0.27 * | 0.64 ± 0.03 | 99.33 ± 6.38 | 10.36 ± 1.49 | 7.15 ± 0.69 * |
VIL, 30 mg/kg | 3.26 ± 0.10 * | 0.46 ± 0.04 | 109.67 ± 5.23 * | 13.13 ± 0.95 | 8.41 ± 0.43 * |
1, 30 mg/kg | 1.79 ± 0.21 # | 0.58 ± 0.02 | 78.30 ± 5.73 # | 9.38 ± 1.25 | 5.16 ± 0.52 # |
3, 30 mg/kg | 2.80 ± 0.25 * | 0.64 ± 0.06 | 90.48 ± 8.6 | 10.78 ± 1.38 | 6.58 ± 1.06 |
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Kuranov, S.; Luzina, O.; Khvostov, M.; Baev, D.; Kuznetsova, D.; Zhukova, N.; Vassiliev, P.; Kochetkov, A.; Tolstikova, T.; Salakhutdinov, N. Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity. Pharmaceuticals 2020, 13, 404. https://doi.org/10.3390/ph13110404
Kuranov S, Luzina O, Khvostov M, Baev D, Kuznetsova D, Zhukova N, Vassiliev P, Kochetkov A, Tolstikova T, Salakhutdinov N. Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity. Pharmaceuticals. 2020; 13(11):404. https://doi.org/10.3390/ph13110404
Chicago/Turabian StyleKuranov, Sergey, Olga Luzina, Mikhail Khvostov, Dmitriy Baev, Darya Kuznetsova, Nataliya Zhukova, Pavel Vassiliev, Andrey Kochetkov, Tatyana Tolstikova, and Nariman Salakhutdinov. 2020. "Bornyl Derivatives of p-(Benzyloxy)Phenylpropionic Acid: In Vivo Evaluation of Antidiabetic Activity" Pharmaceuticals 13, no. 11: 404. https://doi.org/10.3390/ph13110404