성균관대학교 약학대학
천연물 약품화학 실험실
석사 1기 김윤식
Stilbenoids are fonned by a particular branch of the flavonoid
biosynthetic pathway.
They are of special interest to natural product researchers for their
roles in plant resistance to fungal pathogens and their biological
effects.
This review in the volume of Bioactive Natural Products provides a
comprehensive account of the occurrence, chemistry, biological roles
and activities of the stilbenoids.
Nearly 800 stilbenoids, isolated from natural sources in the recent 12
years, are grouped into structural types and discussed in tenns of
their reported phannacological activity.
The major groups of stilbenoids which are discussed in detail include
stilbenes, bibenzyls, bisbibenzyls, phenanthrenoids, stilbene oligomers
etc.
Detailed tables and figures list the occurrence of stilbenoids in major
plant species, and methods used for extracting and analyzing
stilbenoids are discussed.
Biosynthetic pathways and chemical synthesis are reviewed and the
biological activities of stilbenoids are also addressed.
The coverage of the new structures is from 1994 to 2006.
Stilbenoids were first isolated from the plants in 1899 and were
named by Gorham in 1980.
With the chemical diversity and expanded findings of their
bioactivities, stilbenoids are attracting increasing interest across the
world, especially after the hot findings of combretastatin A-4(816) and
resveratrol(1), which shows promising chemo preventive effects
against cancer.
.
A pro-drug of combretastatin A-4 (816), the water soluble phosphate
derivative, is now in phase II of clinical trials.
The number of stilbenoids found in plants, is now in excess of 1000,
compared with just over 100 listed in 1980, and about 300 in 1995.
.
Herein, we review the recent progress in the studies of stilbenoids
with respect to their structure, distribution, extraction and isolation,
technologies used in structure identification, synthesis and
biosynthesis, and the last but not the least, bioactivities
Stilbenes
Other
stilbenoids
Bibenzyls
STILBENOIDS
.
Stilbene
oligomers
Bisbibenzyls
Phenanthrenoids
2.1 Stilbenes
Group A: simple stilbenes having oxygen functions on the aromatic
rings, including the methylenedioxy derivatives
and glycosides.
Group B: prenylated and geranylated stilbenes, regardless of the
substitution position and including the cyclized derivatives.
.
Group C: aryl benzofuran derivatives.
Group D: carbon substituted stilbenes other than the prenylated and
geranylated ones, the C-giycosides and those in group C.
Group E: hybrid stilbenes can not be attributed to the above groups.
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
(13) 3,4-Dihydroxy-3'-methoxystilbene
(8-11) Phoyunbenes A-D
Pholidota yunnanensis
inhibitory effects on nitric oxide production
liverwort Marchesini bongardiana
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
2.1 Stilbenes
2.1.1 Group A (Simple Stilbene)
.
2.1 Stilbenes
2.1.2 Group B (Prenylated and Geranylated Stilbenes)
.
3-(2,3-Dihydroxy-3-methylbutyl) resveratrol
An enantiomeric mixture in
a probable ratio
of 5:3 for the 2"R and 2"S forms
2.1 Stilbenes
2.1.2 Group B (Prenylated and Geranylated Stilbenes)
.
2.1 Stilbenes
2.1.2 Group B (Prenylated and Geranylated Stilbenes)
2.1 Stilbenes
2.1.3 Group C (aryl benzofuran derivatives)
2.1 Stilbenes
2.1.3 Group C (aryl benzofuran derivatives)
2.1 Stilbenes
2.1.4 Group D (Carbon Substituted Stilbenes Other Than Those in Groups 3 and 5)
2.1 Stilbenes
2.1.5 Group E (hybrids)
Seeds of Aiphanes aculeata Willd
Gnetum klossii
2.1 Stilbenes
2.1.5 Group E (hybrids)
2.1 Stilbenes
2.1.5 Group E (hybrids)
Macaranga schweinfurthii (Euphorbiaceae)
2.2 Bibenzyls
Liverworts are rich sources of bibenzyls.
In this review, bibenzyls are classified into four groups:
Group A : simple bibenzyls having oxygen functions on the aromatic rings,
including the methylenedioxy derivatives and glycosides.
Group B : prenylated, geranylated and farnesylated bibenzyls, regardless of
the substitution position.
Group C : 4-hydroxybenzyl substituted bibenzyls.
Group D: other bibenzyls, including aryl-dihydrobenzofurans, phthalides,
dihydroisocoumarins, etc.
2.2 Stilbenes
2.2.1 Group A (Simple Bibenzyls)
Stemona collinsae roots
2.2 Stilbenes
2.2.1 Simple Bibenzyls (Group A)
leaves of Empetrum nigrum
Liverwort Plagiochila spinulosa
2.2 Stilbenes
2.2.1 Simple Bibenzyls (Group A)
Scorzonera humilis (Asteraceae)
2.2 Stilbenes
2.2.2 Prenylated, Geranylated and Famesylated Bibenzyls (Group B)
leaves of Glycyrrhiza lepidota
Anti-viral activity
2.2 Stilbenes
2.2.2 Prenylated, Geranylated and Famesylated Bibenzyls (Group B)
roots of Bauhinia malabarica Roxb
2.2 Stilbenes
2.2.3 4-hydroxybenzyl substituted bibenzyls (Group C)
tubers of Pleione bulbocodioides
2.2 Stilbenes
2.2.4 Other Bibenzyls (Group D)
2.2 Stilbenes
2.2.4 Other Bibenzyls (Group D)
2.3 Bis(bibenzyls)s or bisbibenzyls
Liverworts are rich sources of bisbibenzyls compounds.
Liverworts are a group of plants belonging to the bryophytes.
DNA analysis has revealed that liverworts are the earliest land plants.
Since the isolation of marchantin A (812) from Marchantia and of riccardin A
from Riccardia species by Asakawa et al., more than 100 macrocyclic
. bisbibenzyls including their dimers have been isolated. So far, there have
been nearly 70 bisbibenzyls identified since 1994.
The occurrence of bisbibenzyls in both pteridophytes and liverwort is
very important in determining the evolutionary ladder of both terrestrial
spore-forming green plants.
2.3 Bis(bibenzyls)s or bisbibenzyls
(239, 241) Taiwanese liverwort Reboulia hemisphaerica
(242, 243) Marchantia chenopoda cultivated in Venezuela
2.3 Bis(bibenzyls)s or bisbibenzyls
Chinese liverwort
Marchantia polymorpha L. (Marchantiaceae)
2.3 Bis(bibenzyls)s or bisbibenzyls
2.3 Bis(bibenzyls)s or bisbibenzyls
Pholidota yunnanensis
2.3 Bis(bibenzyls)s or bisbibenzyls
2.4 Phenanthrenoids
2.4.1 Phenanthrenes
2.4 Phenanthrenoids
2.4.1 Phenanthrenes
wetland plant Juncus acutus
2.4 Phenanthrenoids
2.4.2 9,10-dihydroxyphenanthrenes
underground parts of Stemona cf. pierrei
2.4 Phenanthrenoids
2.4.2 9,10-dihydroxyphenanthrenes
The orchid Agrostophyllum callosum
2.4 Phenanthrenoids
2.4.2 9,10-dihydroxyphenanthrenes
two species of Juncus genus
2.4 Phenanthrenoids
2.4.2 9,10-dihydroxyphenanthrenes
2.4 Phenanthrenoids
2.4.3 Dimeric Phenanthrenoids
Allelocheinical interaction, between the
wetland plant Juncus acutus and microalgae
2.4 Phenanthrenoids
2.4.3 Dimeric Phenanthrenoids
Symmetrical dimers
Unsymmetrical manner
2.4 Phenanthrenoids
2.4.4 Phenanthrene Alkaloids
Naturally occurring aristolactams, aristolochic acids and dioxoaporphines;
having a phenanthrene chromophore, are a small group of compounds
mainly found in the Aristolochiaceae.
They have also been reported from plants of the Annonaceae,
Monimimaceae, Menispermaceae and Piperaceae.
2.4 Phenanthrenoids
2.4.5 Other Phenanthrenoids
2.5 Stilbene Oligomers
Structural identification and NMR characterization of stilbene oligomers
still remain a difficult task due to complicated structures and sometime
confusing stereochemistry that comprises many diastereomers, epimers, and
even example of rotational isomers.
The distribution of stilbeneoligomers has been mainly found in the
following families: Dipterocarpaceae, Gnetaceae, Vitaceae, Cyperaceae,
Leguminosae, Moraceae, Welwitschiaceae, Umbelliferae, lridaceae,
Celastraceae, Paeoniaceae and Haemodoraceae.
They are usually accompanied by their monomers.
Dipterocarpaceae, Gnetaceae and Vitaceae all constitute a significant number
of oligostilbenes.
2.5 Stilbene Oligomers
2.5.1 Stilbene Dimers
Gnetum montanum
2.5.1 Stilbene Dimers
2.5.1 Stilbene Dimers
2.5.1 Stilbene Dimers
Maackia amurensls
2.5.2 Stilbene Trimers
roots of Sophora leachiana
2.5.2 Stilbene Trimers
Stem of Kobresia nepalensis (Cyperaceae)
2.5.2 Stilbene Trimers
2.5.2 Stilbene Trimers
Vitis thunbergii
Sophora davidii
2.5.2 Stilbene Trimers
Foeniculum vulgare Miller
2.5.3 Stilbene Tetramers
The genus Caragana
of Leguminosae
2.5.3 Stilbene Tetramers
X2
stems of Vilis davidii
2.5.3 Stilbene Tetramers
Roots of Vitis amurensis
2.5.3 Stilbene Tetramers
Stem bark of Shorea uliginosa
2.5.4 Other Oligomers
Resveratrol pentamer
Resveratrol hexamer
Resveratrol octamer
2.6 Other Stilbenoids
2.6.1 Oligostilbene Derivatives
2.6 Other Stilbenoids
2.6.2 Flavonostilbenes
Stem of Gnetum africanum and the root of G. gnemon
2.6 Other Stilbenoids
2.6.2 Flavonostilbenes
Roots of Sophora a!opixuroides
2.6 Other Stilbenoids
2.6.3 Stilbenolignans
2.6 Other Stilbenoids
2.6.4 Others
Root bark of Artocarpus rigida
It is the development of separation and identification techniques that
makes the isolation and elucidation of the stilbenoids applicable.
Silica gel is still the most commonly used material of the stationary phase.
However, many other materials possessing better resolution or different
isolation mechanisms have also been widely applied, e.g. Sephadex LH-20,
ODS C18, MCI gel CHP20P, Toyopearl HW-40F, especially the former two.
The combination use of the materials is efficient for the separation of the
structures with high similarity and high polarity such as stilbene glucoside
sulfates.
The application of high performance liquid chromatography (HPLC) is very
common in the isolation and analysis procedures.
The application of high performance liquid chromatography (HPLC) is very
common in the isolation and analysis procedures.
Other methods have also been successfully employed in the isolation
procedure of stilbenoids, including MPLC, preparative TLC, centrifugal
partition chromatography(CPC), and the support-free technique of multilayer
coil countercurrent chromatography (MLCCC).
A method based on capillary electrophoresis with electrochemical detection
(CE-ED) was employed for the determination of oligomeric stilbenes found in
the roots of Caragana species.
The direct coupling of HPLC and 1H NMR spectroscopy is a straight forward,
analytical technique which is being used more and more frequently to assign
structures of natural products, avoiding time consuming isolation.
Nowadays, LC-MS systems have been often applied to identify and quantify
stilbenoids
HPLC-CD experiments were carried out in the studies of isoplagiochins C
and D (261, 262) and their analogs' stereochemistry
NMR fingerprinting and GC-MS techniques have also been used in the '
analysis of bibenzyls.
Eluent wall technique-overpressured layer chromatography (FEW-OPLC) has
been successfully employed in the detection of red wine constituents
High resolution NMR (especially 2D NMR techniques, e.g. HMBC, HMQC,
HSQC, COSY, TOCSY, NOESY, ROESY etc.) and HR-MS are indispensable
nowadays making the structure elucidation ' feasible and efficient.
4.1 X-Ray Crystallography
X -ray crystallography is very useful to provide structural information and to
solve the configuration confusions. Many structures of the stilbenoids have
been established with the help of X-ray crystallography.
4.2 Conformational Studies
The' coexistence of the enantiomeric conformations of macrocyclic
bisbibenzyls was detected by X-ray crystallography, NMR and chiral HPLC
experiments.
Isoplagiochins C and D (261 and 262) are intriguing optically active
molecules, which do not possess any kind of traditional chiral centers.
5.1 Biosynthesis of stilbenes
5.2 Biosynthesis of Stilbeneoligomers
5.3 Biosynthesis of Bisbibenzyls
5.4 Biosynthesis of 9,10-Dihydrophenanthrene
Bibenzyls are bicyclic intermediates and require O-methylation as a
prerequisite for their conversion into dihydrophenanthrenes
5.5 Biosynthesis of Other stilbenoids
Lin et al. proposed that the seven artocarpols containing an oxepin ring
stem from appropriate hydroxyl stilbenes
 Suzuki cross-coupling
 Heck coupling
 Perkins condensation
7.1 Anti-Microbial Activity
7.1.1 Antifungal
liverwort Bazzania trilobata
IC50 = (271)3.9, (267)4.0, (283)2.6 μg/mL
7. Anti-Microbial Activity
7.1.2 Antibacterial
Artocarpus lakoocha (Monkey Jack)
Antimycobacterial activity with the MIC values of 12.5 and 50 μg/mL
7. Anti-Microbial Activity
7.1.3 Anti-virus
Leaves of Glycyrrhiza lepidota (American Licorice)
Anti-viral activity with an EC50 of 2.0 μg/ml and an IC50 of 5.0 μg/ml
7. Anti-Microbial Activity
7.2 Anticancer
Cytotoxicity assay is the most commonly used preliminary, anticancer
protocol.
The anticancer effects of the stilbenoids usually involve directing
cytotoxicity, inhibition of the proliferation or inducing apoptosis of the
tumor cells.
7. Anti-Microbial Activity
7.2 Anticancer
In phase II of clinical trials
7. Anti-Microbial Activity
7.2 Anticancer
1000 times stronger
than etoposide
Potent inhibitory activity
than daunorubicin
eight times stronger
than daunorubicin
7. Anti-Microbial Activity
7.3 Anti-lnflammation and Immunomodulating Activity
8-11 inhibited NO production in RAW 264.7
without cytotoxicity
7. Anti-Microbial Activity
7.3 Anti-lnflammation and Immunomodulating Activity
Inhibitory effect on the formyl-peptide stimulated
superoxide anion formation in neutrophils
(IC50 26.0 μM)
(IC50 20.9 μM)
7. Anti-Microbial Activity
7.4 Antioxidant Activity
(1) reduce or diminish oxidative stress
and provide cardiovascular protection
Most stilbenoids possess antioxidant activities because they possess
polyphenol functions in the molecules.
Some of their beneficial effects, hepatoprotective action, cardiovascular
protection, for instance, are in close relation to their antioxidant activities.
7. Anti-Microbial Activity
7.4 Antioxidant Activity
7. Anti-Microbial Activity
7.4 Antioxidant Activity
Lipid peroxide inhibition and superoxide dismutases (SOD) like antioxidant activity
7. Anti-Microbial Activity
7.5 Phytotoxicity
Many phenanthrenes and 9,10-dihydrophenanthrenes isolated by
DellaGreca et al. from the Juncus genus, demonstrated allelochemical
activity against algal pests.
Gigantol and batatasin III as well as synthetic analogs were tested for
phytotoxicity in axenic cultures of the small aquatic plant. Lemna pausicostata
The results suggest that orchid bibenzyls may be good lead compounds for
the development of novel herbicidal agents
7. Anti-Microbial Activity
7.6 Ecdysteroid Antagonistic Activity
7. Anti-Microbial Activity
7.7 Estrogenic/ Antiestrogenic Activities
Resveratrol has a structural similarity to diethylstilbestrol, a synthetic
estrogen.
Therefore, the effect of resveratrol on estrogen receptors (ER) has been
evaluated although the results obtained are inconsistent.
7. Anti-Microbial Activity
7.8 Neuroprotective
(139) stilbostemin B 3'-β-D-glucopyranoside
(140) stilbostemin H 3'-β-D-glucopyranoside
(204) stilbostemin I 2“-β-D-glucopyranoside
7. Anti-Microbial Activity
7.9 Antiplatelet Activity
Roots of Vitis thunbergii
7. Anti-Microbial Activity
7.10 Antidiabetic
The antidiabetic-activity-guided fractionation of cultivated Korean
Rhubarb rhizomes (Rheum undulatum) led to the isolation of
desoxyrhapontigenin, which could inhibit postprandial hyperglycemia
by 35.8%.
Stilbenes desollyrhapontigenin and rhapontigenin from the rhizoma
of Himalayan rhubarb displayed varying degrees of inhibition of yeast
and mammalian intestinal a-glucosidase
7. Anti-Microbial Activity
7.11 Hepatoprotective and Hepatotoxic Activity
Protective effect of hepatic injury
powerful hepatotoxins
7. Anti-Microbial Activity
7.12 Spasmolytic Activity
Bibenzyl and phenanthrenes have been found to possess
smooth muscle relaxant effects
7.13 Other
 Antimutagenic activity
7. Anti-Microbial Activity
7.13 Other
 Stimulation of osteopath growth activity