Structure of Salvianolic acid A
CAS No.: 96574-01-5
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Salvianolic acid A, a natural product isolated and purified from the root of Salvia miltiorrhiza Bge. with antioxidant and protective activity, significantly improves glucose metabolism and inhibit oxidative injury as well as protect against impaired vascular responsiveness in STZ-induced diabetic rats, inhibits platelet activation via the inhibition of PI3K, and attenuates arterial thrombus formation in vivo, suggesting that it may be developed as a therapeutic agent for the prevention of thrombotic disorders. Salvianolic acid A is also a matrix metalloproteinase-9 inhibitor, can prevents cardiac remodeling in spontaneously hypertensive rats, and inhibits PDGF-BB-activated HSC proliferation, partially through apoptosis induction while exerting no direct cytotoxicity on primary hepatocytes and HSC-T6 cells under experimental concentrations.
Synonyms: Salvianolic Acid; Dan Phenolic Acid A
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Discovery of Polyphenolic Natural Products as SARS-CoV-2 Mpro Inhibitors for COVID-19
Krueger, Nadine ; Kronenberger, Thales ; Xie, Hang ; Rocha, Cheila ; Poehlmann, Stefan ; Su, Haixia , et al.
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chem. phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 Mpro. Several compounds were discovered to inhibit Mpro at low micromolar concentrations It was possible to crystallize robinetin together with SARS-CoV-2 Mpro, and the X-ray structure revealed covalent interaction with the protease's catalytic Cys145 site. Selected potent mols. also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for future COVID-19 research.
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Keywords: COVID-19 ; antivirals ; coronavirus ; covalent drugs ; dynamic light scattering ; inhibitors ; main protease ; natural products
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Purchased from AmBeed: 20554-84-1 ; 18524-94-2 ; 568-73-0 ; 989-51-5 ; 484-12-8 ; 86404-04-8 ; 491-70-3 ; 2752-65-0 ; 6147-11-1 ; 10083-24-6 ; 50-81-7 ; 2752-65-0 ; 522-12-3 ; 529-44-2 ; 529-53-3 ; 546-43-0 ; 501-36-0 ; 28957-04-2 ; 4674-50-4 ; 477-43-0 ; 553-21-9 ; 96829-58-2 ; 96574-01-5 ; 20283-92-5 ; 490-31-3 ; 17912-87-7 ; 520-31-0 ; 86404-04-8
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CAS No. : | 96574-01-5 |
Formula : | C26H22O10 |
M.W : | 494.45 |
SMILES Code : | O=C(O)[C@H](OC(/C=C/C1=CC=C(O)C(O)=C1/C=C/C2=CC=C(O)C(O)=C2)=O)CC3=CC=C(O)C(O)=C3 |
Synonyms : |
Salvianolic Acid; Dan Phenolic Acid A
|
MDL No. : | MFCD08458447 |
InChI Key : | YMGFTDKNIWPMGF-UCPJVGPRSA-N |
Pubchem ID : | 5281793 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
In Vitro:
Concentration | Treated Time | Description | References |
C3H10T1/2 adipocytes | 80 µM | 0, 2, 4, 8 hours | To examine the time-course effects of Sal A on UCP-1 expression, results showed that UCP-1 expression significantly increased at 2 h, peaked at 4 h, and returned to basal levels at 8 h | Front Pharmacol. 2021 May 28;12:614406 |
HEK293/ET AR cells | 5.7 µM (IC50) | 10 min | Evaluate the antagonistic effect of Sal A on ET AR, results showed Sal A is a selective ET AR antagonist | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
HepG2 cells | 25, 50, 100 µM | 12 hours | To evaluate the protective effects of Salvianolic acid A against palmitic acid-induced hepatocyte cytotoxicity. Results showed that Salvianolic acid A pretreatment significantly ameliorated palmitic acid-induced cell death. | Front Pharmacol. 2020 Nov 30;11:560905 |
H9c2 cardiomyocytes | 5, 10, 20, 40 µM | 12 hours | To evaluate the protective effects of Salvianolic acid A against palmitic acid-induced cardiomyocyte injury. Results showed that Salvianolic acid A significantly reversed PA-induced cell death, improved mitochondrial membrane potential and intracellular reactive oxygen species levels. | Front Pharmacol. 2021 Mar 8;12:627123 |
HeLa cells | 3.14 µM (IC50) | 15 min | Evaluate the inhibitory effect of Sal A on endogenous ET AR, results showed Sal A partially inhibited ET AR activation | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
HiPS-CMs cells | 10 µM | 24 hours | Evaluate the cytotoxicity of Sal A on hiPS-CMs cells, results showed Sal A had no significant cytotoxicity | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
RAW264.7 cells | 15 and 30 µM | 24 hours | To evaluate the effect of SAA on M2-like TAM polarization, results showed SAA increased the expression levels of CD86, IL-1β, and iNOS, and decreased the expression levels of Arg-1 and CD206. | Molecules. 2024 Mar 26;29(7):1469 |
ARPE-19 cells | 20 µM | 24 hours | To evaluate the cytotoxicity of RGD-PEI/SAA complexes, results showed that low concentrations of SAA (≤20 µM) had no obvious cytotoxic effect, and SAA in nanoparticle form was less toxic than free SAA. | J Nanobiotechnology. 2021 Jul 2;19(1):196 |
Human primary chondrocytes | 10, 20, 40, 80 µg/mL | 24 hours | To evaluate the effect of Salvianolic acid A on cell viability. Results showed no significant cytotoxicity at concentrations ≤80 µg/mL, and SAA significantly suppressed IL-1β-induced inflammatory factors (MMP1, MMP13, ADAMTS-5) expression while promoting collagen II and aggrecan synthesis. | Drug Des Devel Ther. 2020 May 8;14:1771-1778 |
HUVECs | 25 µM | 24 hours | To investigate the effect of Salvianolic acid A on high glucose-induced pyroptosis in endothelial cells. Results showed that SAA inhibited PKM2 Y105 phosphorylation, reduced nuclear translocation of PKM2, thereby suppressing NLRP3 inflammasome activation and endothelial cell pyroptosis. | Front Pharmacol. 2022 Nov 8;13:1009229 |
Mouse chondrocytes | 6.25, 12.5, 25 µM | 24 hours | To evaluate the inhibitory effect of SAA on IL-1β-induced inflammatory response and cartilage matrix degradation. Results showed that SAA significantly inhibited the production of inflammatory mediators (NO, PGE2, TNF-α, IL-6, iNOS, COX-2) induced by IL-1β and reduced the degradation of cartilage matrix. | Front Pharmacol. 2020 Jun 3;11:682 |
HL60 cells | 25 µM | 24 hours | Combination treatment of Sal A and ATO significantly enhanced ATO-induced cytotoxicity | Front Pharmacol. 2018 May 9;9:487 |
K562 cells | 25 µM | 24 hours | Combination treatment of Sal A and ATO significantly enhanced ATO-induced cytotoxicity | Front Pharmacol. 2018 May 9;9:487 |
HepaRG cells | 25 µM | 24 hours | Combination treatment of Sal A and ATO significantly enhanced ATO-induced cytotoxicity | Front Pharmacol. 2018 May 9;9:487 |
SGC7901 cells | 25 µM | 24 hours | Combination treatment of Sal A and ATO significantly enhanced ATO-induced cytotoxicity | Front Pharmacol. 2018 May 9;9:487 |
LX2 cells | 25 µM | 24 hours | To investigate the effect of SalA on PDGF-BB-induced fibrosis and ER stress in LX2 cells, results showed that SalA inhibited ER stress and fibrosis by up-regulating SIRT1 | Front Pharmacol. 2018 Nov 5;9:1277 |
HK-2 cells | 3, 10, 30 µM | 24 hours | To evaluate the inhibitory effect of SAA on LPS-induced inflammatory response in HK-2 cells. Results showed that SAA significantly reduced the secretion of TNF-α and IL-1β and inhibited the activation of NF-κB and p38 MAPK signaling pathways. | Acta Pharmacol Sin. 2018 Dec;39(12):1855-1864 |
H9c2 cells | 12.5 µM | 24 hours | Significantly reduced oxidative stress, ferroptosis and CD36 expression, while increasing p-AMPK | Burns Trauma. 2024 Apr 9;12:tkad055 |
AML12 cells | 10 µM | 24 hours | To evaluate the protective effect of Salvianolic acid A on APAP-induced hepatotoxicity, results showed that Salvianolic acid A significantly increased cell viability and alleviated oxidative stress and inflammation. | Antioxidants (Basel). 2023 Apr 3;12(4):870 |
Primary rat cortical neurons | 50 µM | 24 hours | To evaluate the inhibitory effect of Salvianolic acid A on hemin-induced ferroptosis in primary cortical neurons. Results showed that Salvianolic acid A significantly improved cell viability, reduced intracellular ROS production, decreased MDA and Fe2+ levels, and increased the expression of GSH, XCT, and GPX4. | Sci Rep. 2024 May 30;14(1):12427 |
Human umbilical vein endothelial cells (HUVECs) | 0.25 µM and 0.5 µM | 24 hours | SalA promoted cell viability and proliferation rate, decreased LDH and ROS levels, increased SOD activity, significantly attenuated endothelial senescence, inhibited cell apoptosis, and reversed the increase in LC3 II/I ratio and NLRP3 accumulation. | Sci Rep. 2024 May 24;14(1):11931 |
Human glioma cell line U87 | 0, 5, 10, 15, 20, 25, 50, 100 µM | 24, 48 hours | To evaluate the effects of Sal A on the viability, proliferation, migration, invasion, and apoptosis of glioma cells. Results showed that Sal A treatment reduced the viability of U87 cells in a dose-dependent manner, inhibited proliferation, migration, and invasion, and promoted apoptosis. | Bioengineered. 2022 May;13(5):11646-11655 |
Human Vascular Smooth Muscle Cells (HVSMC) | 10 µM | 4 hours | To identify protein targets of SAA, transgelin and actin were identified as direct targets of SAA via LC-MS/MS | EBioMedicine. 2018 Nov;37:246-258 |
H9c2 cardiomyocytes | 10 µM | 4 hours | Sal A pretreatment alleviated ATO-induced mitochondrial structural and functional damage | Front Pharmacol. 2018 May 9;9:487 |
C3H10T1/2 adipocytes | 20, 40, 80 µM | 4 hours | To investigate the effects of Sal A on UCP-1 expression, results showed that Sal A upregulated UCP-1 mRNA and protein levels in a dose-dependent manner | Front Pharmacol. 2021 May 28;12:614406 |
HEK293 cells | 2.81 μg/mL | 4 hours and 24 hours | Evaluate the antagonistic effect of Sal A on DOX-induced renal cytotoxicity, results showed Sal A significantly reduced DOX-induced damage to HEK293 cells | J Nanobiotechnology. 2022 Sep 24;20(1):425 |
HUVEC cells | 10 µM | 48 hours | Evaluate the cytotoxicity of Sal A on HUVEC cells, results showed Sal A had no significant cytotoxicity | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
MCF-7/PTX cells | 12 µM | 48 hours | To evaluate the reversal effect of Salvianolic acid A on paclitaxel resistance and its inhibitory effect on cell migration and invasion abilities. Results showed that SAA significantly enhanced the sensitivity of MCF-7/PTX cells to paclitaxel and inhibited cell migration and invasion abilities. | Cancer Biol Ther. 2015;16(9):1407-14 |
Human brain microvascular endothelial cells (HBMECs) | 10 µM | 6 hours | To evaluate the protective effect of SAA on OGD-induced cell viability reduction and degradation of tight junction proteins. Results showed that SAA pretreatment significantly inhibited OGD-induced cell viability reduction and degradation of tight junction proteins (ZO-1, occludin, claudin-5). | Acta Pharmacol Sin. 2021 Mar;42(3):370-381 |
A549 cells | 6.461 µM (IC50) | 72 hours | Evaluate the inhibitory effect of Sal A on A549 cell proliferation, results showed Sal A significantly inhibited cell proliferation | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
DU145 cells | 9.512 µM (IC50) | 72 hours | Evaluate the inhibitory effect of Sal A on DU145 cell proliferation, results showed Sal A significantly inhibited cell proliferation | Int J Mol Sci. 2016 Aug 2;17(8):1244 |
HUVECs | 20 µM | 8 hours | To evaluate the anti-angiogenesis effect of RGD-PEI/SAA complexes, results showed that the RGD-PEI/SAA treatment group exhibited the strongest anti-angiogenesis effect among all groups. | J Nanobiotechnology. 2021 Jul 2;19(1):196 |
In Vivo:
Administration | Dosage | Frequency | Description | References |
Sprague-Dawley rats | MCT-induced pulmonary hypertension model by a single subcutaneous injection of MCT (60 mg/kg) | Oral | 0.3, 1, 3 mg/kg/day | Once daily for 4 weeks | SAA significantly attenuated pulmonary arterial remodeling in MCT-induced PAH rats, likely via activating the BMPRII-Smad pathway and inhibiting apoptosis. | Acta Pharmacol Sin. 2016 Jun;37(6):772-82 |
Zucker diabetic fatty rats | Type 2 diabetes mellitus with atherosclerosis induced by high-fat diet and Vitamin D3 injections | Tail vein injection | 1 mg/kg | Once daily for 6 weeks | To evaluate the therapeutic effects of Salvianolic acid A on type 2 diabetes mellitus with atherosclerosis. Results showed that SAA significantly reduced HbA1c levels, improved lipid disorders, reduced foam cells and cholesterol crystals in aortic tissues, and inhibited NLRP3 inflammasome activation and NF-κB signaling pathway. | Molecules. 2020 Feb 28;25(5):1089 |
C57/BL6 mice | Myocardial ischemia model | Oral | 10 mg/kg | Once daily for one week | To evaluate the protective effects of SAA and SAA-30 on myocardial ischemia, results showed that SAA-30 was more effective than SAA in improving myocardial ischemia symptoms | EBioMedicine. 2018 Nov;37:246-258 |
SD rats | Autologous thrombus stroke model | Oral | 10 mg/kg | Twice daily for 5 days | To evaluate the preventive effect of SAA on cerebrovascular endothelial injury caused by ischemic stroke. Results showed that SAA pretreatment significantly improved neurological deficits, intracerebral hemorrhage, BBB disruption, and vascular endothelial dysfunction. | Acta Pharmacol Sin. 2021 Mar;42(3):370-381 |
Sprague-Dawley rats | Intracerebral hemorrhage model | Intraperitoneal injection | 10 mg/kg | Once daily for 5 days | To evaluate the therapeutic effect of Salvianolic acid A on the intracerebral hemorrhage model in rats. Results showed that Salvianolic acid A significantly improved neurological deficits, reduced brain edema and hematoma volume, decreased iron deposition and neuronal degeneration, and inhibited ferroptosis by activating the Akt/GSK-3β/Nrf2 signaling pathway. | Sci Rep. 2024 May 30;14(1):12427 |
Sprague-Dawley rats | Electrocoagulation-induced autologous thrombus stroke model | Intragastric administration | 10 mg/kg | Once daily for 14 days | SAA administration significantly decreased infarction volume and vascular embolism, and ameliorated pathological injury in the hippocampus and striatum as well as the neurological deficits as compared with the model rats. Furthermore, SAA significantly promoted neural stem/progenitor cells (NSPCs) proliferation, migration and differentiation into neurons, enhanced axonal regeneration and diminished neuronal apoptosis around the ipsilateral subventricular zone (SVZ), resulting in restored neural density and reconstructed neural circuits in the ischemic striatum. | Acta Pharmacol Sin. 2022 Sep;43(9):2212-2225 |
ApoE−/− mice | Diabetic atherosclerosis model | Oral gavage | 10 mg/kg and 20 mg/kg | Once daily for four weeks | To investigate the effect of Salvianolic acid A on diabetic atherosclerosis. Results showed that SAA significantly reduced atherosclerotic plaque formation, inhibited pathological changes in the aorta, and ameliorated diabetic atherosclerosis by suppressing NLRP3 inflammasome activation and endothelial cell pyroptosis. | Front Pharmacol. 2022 Nov 8;13:1009229 |
Sprague-Dawley rats | Bile duct ligation (BDL)-induced liver fibrosis model | Intragastric administration | 10 mg/kg/day and 20 mg/kg/day | Once daily for 3 weeks | To investigate the effect of SalA on BDL-induced liver injury and fibrosis, results showed that SalA attenuated ER stress and liver fibrosis by up-regulating the SIRT1/HSF1 pathway | Front Pharmacol. 2018 Nov 5;9:1277 |
Mice | Diabetic myocardial ischemia-reperfusion injury model | Intravenous injection | 10 mg/kg/h | Continuous infusion | The combined application of low-dose propofol and salvianolic acid A conferred synergistic protective effects against myocardial ischemia-reperfusion injury in diabetes, superior to the use of high-dose propofol alone. | Burns Trauma. 2024 Apr 9;12:tkad055 |
SD rats | Gentamicin-induced AKI model and 5/6 nephrectomy-induced CKD model | Intragastric administration | 10, 20, 40 mg/kg/d | 7 consecutive days (AKI model) or four weeks (CKD model) | Salvianolic acid A improved gentamicin-induced AKI and 5/6 Nx-induced CKD, which may be achieved by inhibiting the release of inflammatory factors and alleviating oxidative stress injury, as well as regulating the MAPKs and TGF-β1/smads signaling pathways. | Molecules. 2023 Apr 21;28(8):3630 |
C57BL/6 mice | APAP-induced hepatotoxicity model | Oral | 15 mg/kg/day and 30 mg/kg/day | Once daily for 3 days | To evaluate the protective effect of Salvianolic acid A on APAP-induced hepatotoxicity, results showed that Salvianolic acid A significantly reduced serum ALT and AST levels and alleviated liver tissue damage. | Antioxidants (Basel). 2023 Apr 3;12(4):870 |
BALB/c nude mice | 4T1 breast cancer model | Tail vein injection | 2 mg/kg DOX and 20 mg/kg Sal A | Once every two days, total of 6 administrations | Evaluate the anti-tumor effect and nephrotoxicity of E-[c(RGDfK)2]/FA-NLC-Sal A/DOX, results showed the best anti-tumor effect (tumor volume inhibition rate 90.72%, tumor weight inhibition rate 83.94%) and low nephrotoxicity (serum creatinine concentration 52.58 μmoL/L) | J Nanobiotechnology. 2022 Sep 24;20(1):425 |
Sprague-Dawley rats | 5/6 nephrectomized rat model | Intraperitoneal injection | 2.5, 5, 10 mg/kg/day | Once daily for 28 days | To evaluate the protective effect of SAA on kidney injury in 5/6 nephrectomized rats. Results showed that SAA dose-dependently reduced the levels of urine protein, blood urea nitrogen, serum creatinine, plasma total cholesterol, and plasma triglycerides, and improved renal pathological lesions and fibrosis. Additionally, SAA inhibited the activation of NF-κB and p38 MAPK signaling pathways and reduced the secretion of inflammatory cytokines. | Acta Pharmacol Sin. 2018 Dec;39(12):1855-1864 |
C57BL/6J mice | Laser-induced choroidal neovascularization model | Intravitreal injection | 20 µM | Single injection, observed for 7 days | To evaluate the anti-angiogenesis effect of RGD-PEI/SAA complexes in a laser-induced CNV mouse model, results showed that the RGD-PEI/SAA treatment group reduced the CNV area by 55.78% compared to the PBS group. | J Nanobiotechnology. 2021 Jul 2;19(1):196 |
C57BL/6J mice | High-fat and high-carbohydrate diet-induced fatty liver model | Intraperitoneal injection | 20 and 40 mg/kg | Every other day for 10 weeks | To evaluate the protective effects of Salvianolic acid A against high-fat and high-carbohydrate diet-induced fatty liver. Results showed that Salvianolic acid A attenuated body weight gain, liver injury, and hepatic steatosis. | Front Pharmacol. 2020 Nov 30;11:560905 |
Male C57BL/6 mice | High-fat diet-induced obesity model | Intraperitoneal injection | 20 and 40 mg/kg | Administered every other day for 13 weeks | To investigate the protective anti-obesity mechanisms of Sal A, results showed that Sal A significantly attenuated weight gain and lipid accumulation, and induced browning of white adipose tissue | Front Pharmacol. 2021 May 28;12:614406 |
BALB/c mice | ATO-induced cardiotoxicity model | Intraperitoneal injection | 3 mg/kg | Once daily for 2 weeks | Sal A pretreatment alleviated ATO-induced cardiac mitochondrial damage | Front Pharmacol. 2018 May 9;9:487 |
C57BL/6J mice | High-fat diet-induced obese mouse model | Intraperitoneal injection | 40 mg/kg | Every other day for 12 weeks | To evaluate the protective effects of Salvianolic acid A against high-fat diet-induced myocardial injury. Results showed that Salvianolic acid A significantly improved myocardium morphological changes and myocardial damage, and reduced plasma AST and CK-MB levels. | Front Pharmacol. 2021 Mar 8;12:627123 |
Sprague-Dawley rats | CCl4-induced liver fibrosis model | Intraperitoneal injection | 5 mg/kg and 15 mg/kg | Once daily for 6 weeks | To evaluate the therapeutic effect of salvianolic acid A on CCl4-induced liver fibrosis. The results showed that salvianolic acid A significantly reduced the degree of liver fibrosis, improved liver function indicators, reduced collagen deposition, and inhibited hepatic stellate cell activation and hepatocyte apoptosis by inhibiting the PI3K/AKT/mTOR signaling pathway and regulating the Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways. | Drug Des Devel Ther. 2019 May 31;13:1889-1900 |
BALB/c mice | Pristane-induced systemic lupus erythematosus model | Oral gavage | 5 mg/kg/d | Once daily for 5 months | To evaluate the protective effect of salvianolic acid A on renal injury in pristane-induced systemic lupus erythematosus mice. The results showed that salvianolic acid A significantly reduced the levels of anti-Sm autoantibodies, alleviated renal histopathological changes, and significantly inhibited the phosphorylation of IKK, IκB and NFκB in renal tissues. | Acta Pharm Sin B. 2017 Mar;7(2):159-166 |
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