| Protoberberine alkaloids, a kind of isoquinolone alkaloids, exist in several genera of the plant families. They have multiple pharmacological activities, especially the antibacterial, analgesic and anti-diabetic activities are the main effects that widely applied in clinic. The difference of the antibacterial, analgesic and anti-diabetic activities among berberine, palmatine, coptisine, jatrorrhizine, corydalis B and rotundine was studied. The mechanism of their function was analyzed by theoretical studies on molecular levels.1. Antibacterial activityThe antimicrobial activity of protoberberines agaist the stardard strains of Gram-positive bacterium(s. aureus and s. epidermidis ) and Gram-negative bacterium (S. flexneri, E.coli and K.pnermoniae ) were tested using disc method with azithromycin and gentamicin as reference in vitro. The results showed that corydalis B exhibited no inhibitory activity against G+ and G- bacterium. The activities of berberine agaist S. aureus and S. epidermidis were about 3 and 10 times greater than that of berberine and jatrorrhizine respectively. Berberine was found to be 1.4 and 10 times more active aganist S. flexneri than coptisine and palmatine respectively. For K .pnermoniae, only berbeine and coptisine have antibacterial activities and the activity of berberine is 1.9 times than that of coptisine.Structures analysis revealed that quaternary nitrogen is essential to antibacterial activity and the methylenedioxy group at the C2 and C3 is required for enhanced activity. The 3D structures of berberine , tetracyclines and quinolones have been compared and overlapped well ,which indicated probably their antibacterial mechanism is identical . The mechanism of antimicrobial of protoberberines maybe relate to the inhibition of 3 OS ribosome or DNA gyraseA . Molecular docking revealed that protoberberine alkaloids were not appropriate to DNA gyrase B or sortase B.2. Analgesic activityAfter 1 hour the drugs were administrated, the mice were intraperitoneally injected with 0.2ml of 0.6% acetic acid solution. The numbers of writhing reflex were counted for 15 minutes after the acetic acid injection. Rotundine , corydalis B and berberine could inhibit writhing movements of mice and the inhibitory rate of rotundine ,corydalis B, berberine ,palmatine and coptisine is 98.4, 92.7, 40.8, 26.7, 11.0% respectively. Licking paw time was measured before administration and 30,60,120min after single orally administrated. At dose of 50mg/kg ,rotundine and corydalis B had effects on mice licking paw time, but berberine, palmatine and coptisine have no effect at dose of 150mg/kg.Rotundine and corydalis B of tetrahydroprotoberberines showed strong analgesic activity induced by chemical and heat stimulation. Theoretical calculation demonstrated that the dihedral angle of ring B and C and the bond lengths of N-C8, N-C14 strongly changed after reduction of the ring C, which lead to the three-dimensional structure changed strongly, thus the analgesic activity increased . The analgesic mechanism of tetrahydroprotoberberines was different to the other compounds, probably it is concerned to the central mechanism. The docking of other prtoberbennes with cyclo-oxygenase is rational ,which suggested the other alkoloidsof the proberberines maybe act as the cyclo-oxygenase inhibitors. Molecular dynamics simulations had been performed in Hyperchem 7.0, the results showed the protoberines mainly combined to Cox2 by Van der Waals , and the effects of substituent groups of 2,3 and 9,10 have different effects during ligand-receptor docking, which maybe relat to the analgesic activity induced by acetic acid.3. Antidiabetic activityDiabetic mice models were made after iv injected alloxan at dose of 80mg/kg. After orally administrated for 5 days , the blood samples were collected 2h after administration for determining fasting blood glucose with glucose oxidase method. Berberine and coptisine have anti-diabetic activities at dose of 200mg/kg. There was no significant difference of lowering glucose among b... |
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