Derivatives of schisandrin with increased inhibitory potential on prostaglandin E(2) and leukotriene B(4) formation in vitro.
Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB(4) production the IC(50) values of aR-6,7-dihydro-6-(1'-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1'-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2+/-0.3microM and 4.5+/-0.2microM, respectively. aR-6,7-Dihydro-6-(1'-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC(50) 32.1+/-2.5microM) and on LTB(4) production (37.3+/-5.5% inhibition at 50microM).
Blunder
Martina
M
Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitaetsplatz 4, 8010 Graz, Austria. martina.blunder@uni-graz.at
Pferschy-Wenzig
Eva M
EM
Fabian
Walter M F
WM
Hüfner
Antje
A
Kunert
Olaf
O
Saf
Robert
R
Schühly
Wolfgang
W
Bauer
Rudolf
R
D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002942:Circular Dichroism; D034242:Cyclooctanes / Q000138:chemical synthesis* / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007202:Indicators and Reagents; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D017705:Lignans / Q000138:chemical synthesis* / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D032141:Schisandra / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D034242:Cyclooctanes; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D017705:Lignans; D016859:Lipoxygenase Inhibitors; D011083:Polycyclic Compounds; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; C011105:schizandrin; D015232:Dinoprostone