Rupestonic acid

Structural modification on rupestonic acid leads to highly potent inhibitors against influenza virus.[Pubmed:29971616]

Mol Divers. 2019 Feb;23(1):1-9.

Influenza viruses are responsible for seasonal epidemics and occasional pandemics, which cause significant morbidity and mortality. Although several drugs (adamantanes and neuraminidase inhibitors) are available in the market, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs. Artemisia rupestris L. is a folk medicine used to treat cold. In this paper, we structurally modified Rupestonic acid, a bioactive component of A. rupestris, to synthesize a series of 2-substituted Rupestonic acid methyl esters (3a-3o). Their structures were fully characterized by (1)H NMR, (13)C NMR, HRMS spectra. Among them, compounds 3b and 3c exhibited potent activities against influenza H1N1 with micromolar IC50 values and might serve as new lead compounds for the treatment of influenza.

Asymmetric Synthesis of Rupestonic Acid and Pechueloic Acid.[Pubmed:29211481]

Org Lett. 2017 Dec 15;19(24):6732-6735.

In this report, the originally proposed Rupestonic acid (5) and pechueloic acid (3) were efficiently synthesized. The chiral lactone 13, recycled from the degradation of saponin glycosides, was utilized to prepare the key chiral fragment 11. During the exploration of this convergent assembly strategy, the ring-closing metathesis (RCM), SmI2-prompted intermolecular addition, and [2,3]-Wittig rearrangement proved to be effective transformations for the synthesis of subunits.

Structure-activity relationship studies of 1-(1'-hydroxyalkyl)rupestonic acid methyl esters against influenza viruses.[Pubmed:28196702]

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1484-1487.

A series of 1-(1'-hydroxyalkyl)Rupestonic acid methyl esters were synthesized via the condensation of methyl rupestonate with various aldehydes in the presence of LDA. This mixed aldol reaction was highly stereoselective and all the new compounds were elucidated by detailed NMR and MS analyses. The absolute configurations of the newly formed stereocenters were further confirmed by X-ray crystallographic analysis of 3d, the results of which were found to be opposite to the prediction based on Zimmerman-Traxler's and Houk's models. All the compounds synthesized were then evaluated for their in vitro inhibitory activities against influenza A (H1N1 and H3N2) and B viruses. The data showed that 3p displayed the highest activity against influenza A H1N1 (IC50=0.69mug/mL) and H3N2 (IC50=0.69mug/mL) viruses, which were even better than Ribavirin and Oseltmivir. On the other hand, both 3c and 3o were found to show comparable activities with the reference drugs in inhibiting both influenza A and B viruses. Further studies will focus on reducing the cytotoxicity of the hits reported in this work.

Rupestonic acid derivative YZH-106 suppresses influenza virus replication by activation of heme oxygenase-1-mediated interferon response.[Pubmed:27107768]

Free Radic Biol Med. 2016 Jul;96:347-61.

Given the limitation of available antiviral drugs and vaccines, there remains to be a pressing need for novel anti-influenza drugs. Rupestonic acid derivatives were reported to have an anti-influenza virus activity, but their mechanism remains to be elucidated. Herein, we aim to evaluate the antiviral activity of YZH-106, a Rupestonic acid derivative, against a broad-spectrum of influenza viruses and to dissect its antiviral mechanisms. Our results demonstrated that YZH-106 exhibited a broad-spectrum antiviral activity against influenza viruses, including drug-resistant strains in vitro. Furthermore, YZH-106 provided partial protection of the mice to Influenza A virus (IAV) infection, as judged by decreased viral load in lungs, improved lung pathology, reduced body weight loss and partial survival benefits. Mechanistically, YZH-106 induced p38 MAPK and ERK1/2 phosphorylation, which led to the activation of erythroid 2-related factor 2 (Nrf2) that up-regulated heme oxygenase-1 (HO-1) expression in addition to other genes. HO-1 inhibited IAV replication by activation of type I IFN expression and subsequent induction of IFN-stimulated genes (ISGs), possibly in a HO-1 enzymatic activity-independent manner. These results suggest that YZH-106 inhibits IAV by up-regulating HO-1-mediated IFN response. HO-1 is thus a promising host target for antiviral therapeutics against influenza and other viral infectious diseases.

Computational insights into the inhibition of influenza viruses by rupestonic acid derivatives: pharmacophore modeling, 3D-QSAR, CoMFA and COMSIA studies.[Pubmed:25483013]

Comb Chem High Throughput Screen. 2015;18(1):63-74.

The pharmacophore modeling and 3D-QSAR studies were performed on a series of amino alkyl rupestonates (Rupestonic acid) derivatives reported for H1N1, H3N2 and Influenza B virus, NA inhibition. In order to improve the efficacy of amino alkyl rupestonates derivatives, a four point pharmacophore model with one acceptor and three hydrophobic regions was developed. Furthermore, the 3D-QSAR model was generated based on the pharmacophore hypothesis (AHHH) for each subtype. The hypothesis was more significant with R(2)=0.9204, Q(2)=0.917 for H1N1, R(2)=0.8911, Q(2)=0.8905 for H3N2 and R(2)=0.8385, Q(2)=0.7043 for Influenza B virus. The 3D-QSAR results provided an invaluable insight into structure activity correlation and it was shown that the hydrophobic regions were crucial for inhibitory activity. CoMFA and COMSIA validation had been done by leave one out and no validation methods.

Identification of metabolites of rupestonic acid in rat urine by liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry.[Pubmed:25187340]

Biomed Chromatogr. 2015 Apr;29(4):595-603.

Rupestonic acid, a potential anti-influenza agent, is an important and characteristic compound in Artemisia rupestris L., a well-known traditional Uighur medicine for the treatment of colds. In the present study, high-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry was used to detect and identify the metabolites in rat urine after oral administration of Rupestonic acid. A total of 10 metabolites were identified or partially characterized. The structure elucidations of the metabolites were performed by comparing the changes in accurate molecular masses and fragment ions with those of the parent compound. The results showed that the main metabolites of Rupestonic acid in rat urine were formed by oxidation, hydrogenation and glucuronidation. A metabolism pathway was proposed for the first time based on the characterized structures. This metabolism study can provide essential information for drug discovery, design and clinical application of Rupestonic acid.

Rupestonic acids B-G, NO inhibitory sesquiterpenoids from Artemisia rupestris.[Pubmed:25127164]

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4318-22.

Six new guaiane sesquiterpenoids, Rupestonic acids B-G (1-6), have been isolated from the whole plants of Artemisia rupestris together with six known compounds (7-12). The structures of the new isolates (1-6) were elucidated on the basis of extensive 1D and 2D NMR analysis, and the absolute configurations were established by electronic circular dichroism (ECD) in combination with density functional theory calculations. In in vitro bioassays, compounds 2 and 6 exhibited significant inhibitory effects on LPS-stimulated NO production in BV-2 microglial cells with IC50 values of 2.6 and 2.2 muM, respectively.

1,2,3-Triazole-containing derivatives of rupestonic acid: click-chemical synthesis and antiviral activities against influenza viruses.[Pubmed:24583605]

Eur J Med Chem. 2014 Apr 9;76:245-55.

Two series of Rupestonic acid derivatives, (1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylate and N-(1-substituted-1H-1,2,3-triazol-4-yl)methyl 2-((5R,8S,8aS)-3,8-dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octahydroazulen-5-yl)acrylamid e were easily and efficiently synthesized via click chemistry. These compounds were tested for their in vitro activities against various strains of influenza A virus (H1N1, oseltamivir resistant H1N1, H3N2) and influenza B virus. The results showed that nine compounds were active against the H1N1 strain of influenza A virus and among them the best one 14a, was as active as the reference drugs, Oseltamivir and Ribavirin. Some of them were also active on the Oseltamivir resistant H1N1 strain. In regards to influenza B virus, twenty-one compounds over thirty were active and seven of them 7b, 8b, 9b, 10a, 11b, 12b, 13b showed better activity than Ribavirin. The structure-activity relationship of these compounds is discussed on the basis of each type of the viruses studied. Furthermore, four best representative compounds 7b, 10a, 12b and 14a were evaluated in a plaque assay experiment using MDCK cells and RBV as control compound and the results showed that 7b, 10a and 12b were better than RBV in inhibiting plaque formation, in good accordance with their anti-influenza B activities.

Quantitative determination of rupestonic acid in rat plasma by high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study.[Pubmed:23037995]

Biomed Chromatogr. 2013 May;27(5):563-7.

A sensitive and specific high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed and validated for determination of Rupestonic acid in rat plasma. Protein precipitation method was used to extract Rupestonic acid and the internal standard (IS) warfarin sodium from rats plasma. The chromatographic separation was performed on an Agela Venusil XBP Phenyl column with an isocratic mobile phase consisting of methanol-0.1% formic acid in water (40:60, v/v), pumped at 0.4 mL/min. Rupestonic acid and the internal standard (IS) warfarin sodium were detected at m/z 247.2 --> 203.1 and 307.1 --> 161.3 in positive ion and multiple reaction monitoring mode respectively. The standard curves were linear over the concentration range of 2.5-5000 ng/mL (r(2) > 0.99). The within-day and between-day precision values for Rupestonic acid at four concentrations were 4.7-5.7 and 4.4-8.7%, respectively. The method described herein was fully validated and successfully applied to the pharmacokinetic study after an intravenous administration of Rupestonic acid in rats.

Advances in studies on the rupestonic acid derivatives as anti-influenza agents.[Pubmed:22625417]

Mini Rev Med Chem. 2013 Feb;13(2):310-5.

Rupestonic acid (isolated from the Chinese traditional medicine Artemisia rupestris L.) is a sesquiterpene with multifunctional groups and possess higher activity against influenza virus B. In order to improve the biological activity of Rupestonic acid, many derivatives have been synthesized and their anti-influenza activity was screened. This review describes the Rupestonic acid derivatives and their anti-influenza activity studied by our researching group.

Synthesis and anti-influenza activity of aminoalkyl rupestonates.[Pubmed:22341943]

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2321-5.

A series of aminoalkyl rupestonates were designed and synthesized by reacting Rupestonic acid with 1,omega-dibromoalkanes, followed by amination. All of the new compounds were bioassayed in vitro to determine their activities against influenza A (H3N2, H1N1) and B viruses. The results showed that compounds 5a-5g, which each contain a 1H-1,2,4-triazolyl moiety, were found to be the most potent set of compounds. Compound 5g was demonstrated to possess the highest inhibitory activity against influenza H3N2 and H1N1, with IC(50) values of 0.97 and 0.42 muM, respectively. Our results also indicated that compounds 2g, 3g, 4g and 5g, which contain ten-CH(2)-unit spacers between the Rupestonic acid and amino functional groups, were the most potent inhibitors of influenza H1N1 among the synthesized compounds. Unfortunately, most of the synthesized compounds did not show an obvious activity against influenza B; the only exceptions were compounds 5d and 5f, which had IC(50) values of 17.3 and 3.2 muM, respectively. Compounds 4g and 5g were potent inhibitors of influenza H1N1, and they might be potentially developed as new lead anti-influenza virus compounds. Further studies of the mechanism of action are underway.

Characterization and identification of chemical compositions in the extract of Artemisia rupestris L. by liquid chromatography coupled to quadrupole time-of-flight tandem mass spectrometry.[Pubmed:22215581]

Rapid Commun Mass Spectrom. 2012 Jan 15;26(1):83-100.

Liquid chromatography coupled to negative electrospray ionization (ESI) tandem mass spectrometry (MS/MS) employing a time-of-flight tandem mass spectrometer was used in the structural determination of phenolic compounds and sesquiterpenoids occurring in the extract from Artemisia rupestris L. A total of 91 compounds including chlorogenic acid derivatives, flavonoids (aglycone, O-glycosyl, C-glycosyl and C,O-glycosyl), 2-phenoxychromones and guaiane sesquiterpenoids were identified by comparing the retention time and fragmentation behavior with reference standards or according to accurate mass measurement and the characteristic fragmentation at low and high collision energy. Most of these compounds were reported in Artemisia rupestris L. for the first time. Meanwhile, the proposed pathway and the major diagnostic fragmentation of 2-phenoxychromone and Rupestonic acid were investigated to trace 2-phenoxychromone and Rupestonic acid derivatives in crude plant extracts. According to these rules, we have successfully characterized five potential novel compounds including three 2-phenoxychromones (6-demethoxy-4'-O-methylcapillarisin-O-hexosylglucuronide, 6-demethoxy-4'-O-methylcapillarisin-O-pentosylhexoside and 6-demethoxy-4'-O-methylcapillarisin-O-deoxyhexosylhexoside) and two sesquiterpenoids (hexosyl-glycurinide-Rupestonic acid and hexoside-Rupestonic acid).

One-step separation and purification of rupestonic acid and chrysosptertin B from Artemisia rupestris L. by high-speed counter-current chromatography.[Pubmed:19821258]

Phytochem Anal. 2010 Mar-Apr;21(2):205-9.

INTRODUCTION: Artemisia rupestris L. is a well-known traditional Chinese medicinal plant in Xinjiang. Rupestonic acid is the main active ingredient of A. rupestris L., and has been chosen as a 'marker compound' for the chemical evaluation or quality control of A. rupestris L. and its products. Although HSCCC separation method was developed before, the separation was performed with two steps using the same solvent system, which were time-consuming and waste of the solvents. OBJECTIVE: To develop a simple HSCCC method for the separation and purification of Rupestonic acid in a single run. METHODOLOGY: The measurement of partition coefficient (K) was introduced to select the two-phase solvent system. The simple HSCCC method was established according to the selected solvent system for separation and purification of Rupestonic acid. The purity of target compound was test by HPLC and the structure was identified by MS, (1)H NMR and (13)C NMR. RESULTS: A total of 72.3 mg of Rupestonic acid and 53.5 mg of chrysosptertin B with over 95% purity were yielded from 500 mg extracts of Artemisia rupestris L. in one-step separation. CONCLUSION: The Rupestonic acid was separated in a single run by HSCCC.

(5R,8R)-2-(3,8-Dimethyl-2-oxo-1,2,4,5,6,7,8,8a-octa-hydro-azulen-5-yl)acrylic acid (rupestonic acid).[Pubmed:21201504]

Acta Crystallogr Sect E Struct Rep Online. 2008 Jan 23;64(Pt 2):o479.

The title compound, C(15)H(20)O(3), crystallizes with two independent mol-ecules in the asymmetric unit. In both mol-ecules, the seven-membered ring adopts a chair conformation. In the crystal structure, inter-molecular O-Hcdots, three dots, centeredO hydrogen bonds link the mol-ecules into chains extending in the [201] direction. The absolute configuration was assigned on the basis of the starting materials.