Isolation of lignans from Schisandra chinensis with anti-proliferative activity in human colorectal carcinoma: Structure-activity relationships.
Separate benzocyclooctadiene lignans were isolated from the berries of Schisandra chinensis in milligram quantities on analytical reverse phase (RP) HPLC by an automated repeat-injection method and shown to have anti-proliferative activity against human colorectal cancer cells. Structures of the compounds were determined by a combination of NMR and mass spectrometry. Stereospecific NMR assignments for gomisin-N and deoxyschisandrin, gave more complete and accurate data than previously reported, based on 600MHz 2D HSQC, DQF-COSY and HMBC data. Comparison of coupling constants and HMBC crosspeak intensities with calculated and X-ray crystal structures confirmed their stereochemistry and conformation. Analysis of structure-activity relationships revealed the importance of key structural determinants. The S-biphenyl configuration of gomisin N, the most active lignan, correlated with increased anti-proliferative activity, while the presence of a hydroxyl group at the C7 position reduced or abolished this activity. Increased activity was also observed when a methylenedioxy group was present between C12 and C13. The percent yield of the most active compounds relative to the starting plant materials was 0.0156% for deoxyschisandrin and 0.0173% for gomisin N. The results of these studies indicate that automated repeat-injection method of analytical HPLC may provide a superior alternative to the standard semi-preparative HPLC techniques for separation of complex mixtures.
Gnabre
John
J
Department of Biology, Johns Hopkins University, Mudd Hall, 3400 N. Charles Street, Baltimore, MD 21218, USA.
Unlu
Irem
I
Chang
Tso-Cheng
TC
Lisseck
Paul
P
Bourne
Bryan
B
Scolnik
Ryan
R
Jacobsen
Neil E
NE
Bates
Robert
R
Huang
Ru Chih
RC
D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D034242:Cyclooctanes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D005638:Fruit / Q000737:chemistry; D019073:HT29 Cells; D006586:Hexanes / Q000737:chemistry; D006801:Humans; D020014:K562 Cells; D017705:Lignans / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D008752:Methylene Chloride / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology; D032141:Schisandra / Q000737:chemistry*; D013329:Structure-Activity Relationship
D034242:Cyclooctanes; D006586:Hexanes; D017705:Lignans; D010936:Plant Extracts; D008752:Methylene Chloride