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
Bisbibenzyls
oligomers

Phenan-
threnoids
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

liverwort Marchesini bongardiana

(8-11) Phoyunbenes A-D

Pholidota yunnanensis
inhibitory effects on nitric oxide production
 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)

. An enantiomeric mixture in
a probable ratio
of 5:3 for the 2"R and 2"S forms

3-(2,3-Dihydroxy-3-methylbutyl) resveratrol
 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 Potent inhibitory activity eight times stronger

than etoposide than daunorubicin 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