Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones
Abstract
:1. Introduction
2. Results
2.1. Chemistry and cLogP
2.2. Evaluation of Vasorelaxant Activity
2.3. Involvement of ERα and NO Pathways
2.3.1. Evaluation of Vasorelaxant Activity on ERα KO Mice Aorta
2.3.2. Evaluation of Vasorelaxant Activity in the Presence of Nω-nitro-L-arginine methyl ester (L-NAME)
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. Calculated logP
4.3. Animals
4.4. Vascular Reactivity
4.5. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACE | Angiotensin converting enzyme |
AlCl3 | Aluminum chloride |
BKCa | Calcium-activated potassium channel-dependent |
brsm | Based on recovered starting material |
cLogP | Calculated octanol-water partition coefficient |
CVDs | Cardiovascular diseases |
DCM | Dichloromethane |
eNOS | Endothelial nitric oxide synthase |
ERα | Estrogen receptor α |
ERβ | Estrogen receptor β |
EtOAc | Ethyl acetate |
EtOH | Ethanol |
HCl | Hydrochloric acid |
K2CO3 | Potassium carbonate |
KO | Knock out |
KOH | Potassium hydroxide |
L-NAME | Nω-nitro-L-arginine methyl ester |
LiOH.H2O | Lithium hydroxide monohydrate |
MOM | Methoxymethyl |
MW | Microwave |
NO | Nitric oxide |
OCH3 | Methoxyl |
OH | Hydroxyl |
PSS | Physiological saline solution |
PKG | Protein kinase G |
RT | Room temperature |
SAR | Structure-activity relationships |
sGC | Soluble guanylyl cyclase |
SOCl2 | Thionyl chloride |
THF | Tetrahydrofuran |
TLC | Thin-layer chromatography |
WHO | World health organization |
WT | Wilde type |
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Compound | R2’ | R4’ | R6’ | R3 | R4 | R5 | cLogP |
3 | OH | OH | H | OCH3 | OH | OCH3 | 2.42 |
6 | OH | OH | OH | OCH3 | OH | OCH3 | 1.80 |
8 | OH | OH | H | OCH3 | OCH3 | OCH3 | 2.75 |
10 | OH | OH | OH | OCH3 | OCH3 | OCH3 | 2.13 |
11 | OCH3 | OCH3 | H | H | OH | H | 3.20 |
12 | OH | OCH3 | H | OCH3 | OH | OCH3 | 2.99 |
13 | OCH3 | OCH3 | H | OCH3 | OH | OCH3 | 2.84 |
14 | OH | OCH3 | H | OCH3 | OCH3 | OCH3 | 3.33 |
15 | OCH3 | OCH3 | H | OCH3 | OCH3 | OCH3 | 3.17 |
16 | OCH3 | OCH3 | OCH3 | OCH3 | OCH3 | OCH3 | 3.13 |
17 | OCH3 | OCH3 | OCH3 | OCH3 | OH | OCH3 | 2.79 |
18 | OH | OCH3 | OCH3 | OCH3 | OH | OCH3 | 2.97 |
20 | OCH3 | OCH3 | H | OCH3 | OCH2COOH | OCH3 | 2.46 |
Compound | Potency (EC50, g/L) WT | Efficacy (Emax, %) | |||
---|---|---|---|---|---|
WT | WT with L-NAME | ERα KO | ERα KO with L-NAME | ||
3 | 2.44 × 10−3 | 84.28 ± 3.24 a,d | 77.62 ± 4.92 | 56.23 ± 4.91 £ | 43.22 ± 6.10 $ |
6 | 2.12 × 10−3 | 57.10 ± 10.40 c,d | 33.92 ± 12.66 | 60.69 ± 10.75 | 38.15 ± 10.91 |
8 | 2.99 × 10−3 | 89.96 ± 4.13 b,c | 86.69 ± 3.47 | 79.73 ± 3.71 | 69.76 ± 7.99 |
10 | 4.08 × 10−3 | 63.29 ± 12.79 a,b | 44.91 ± 15.07 | 52.83 ± 12.88 | 43.33 ± 10.37 |
11 | 1.93 × 10−2 | 67.35 ± 8.94 g | 49.06 ± 9.47 | 74.81 ± 2.07 | 36.40 ± 5.81 |
12 | NA | 30.95 ± 13.23 | NA | NA | NA |
13 | 5.06 × 10−2 | 80.86 ± 6.11 | 19.85 ± 7.81 * | 81.96 ± 2.46 | 26.96 ± 6.72 |
14 | NA | 48.38 ± 7.75 | NA | 4.64 ± 9.95 | NA |
15 | NA | 90.59 ± 1.56 e,f | 76.07 ± 3.72 | 79.78 ± 5.51 | 76.74 ± 5.68 |
16 | NA | 75.89 ± 5.99 f | NA | 74.91 ± 10.15 | NA |
17 | NA | 72.16 ± 4.59 e | NA | 86.88 ± 4.40 | NA |
18 | NA | 24.34 ± 4.60 | NA | NA | NA |
20 | NA | 40.77 ± 8.22g | NA | NA | NA |
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Legeay, S.; Trân, K.; Abatuci, Y.; Faure, S.; Helesbeux, J.-J. Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones. Int. J. Mol. Sci. 2020, 21, 1609. https://doi.org/10.3390/ijms21051609
Legeay S, Trân K, Abatuci Y, Faure S, Helesbeux J-J. Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones. International Journal of Molecular Sciences. 2020; 21(5):1609. https://doi.org/10.3390/ijms21051609
Chicago/Turabian StyleLegeay, Samuel, Kien Trân, Yannick Abatuci, Sébastien Faure, and Jean-Jacques Helesbeux. 2020. "Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones" International Journal of Molecular Sciences 21, no. 5: 1609. https://doi.org/10.3390/ijms21051609