Flavonoid

Batasan
 Golongan fenol alam yang tersebar luas dalam
tumbuhan
 Umumnya terdapat tumbuhan, terikat pada gula
sebagai glikosida dan dalam bentuk campuran
 Kimia flavonoid telah diterapkan dalam berbagai
disiplin ilmu: kemotaksonomi, evolusi tumbuhan,
fitogeografi, hibrida dan pemulihan tanaman,
hama dan penyakit, ekolohi, pengaeatran
makanan dan farmakologi
Phenolics

Group of secondary plant products or

compounds
Composed of a hydroxyl group attached to an
aromatic ring
A broad range of compounds - found in all
components of plants: leaves, flowers, fruit etc
Function of most compounds is unknown
Comprised of many groups: Flavonoids, Tannins,
Lignin etc. All very chemically diverse!
Flavonoids
Water soluble pigment
Most widely studied group of phenolics: over 3000
described
Seem to have major health
benefits for humans - red
wine and cholesterol
Variety of important functions
in plants
Flavonoid Functions
Combine to create flower pigmentation: serve as
signals for pollinators

Block UV radiation destructive to nucleic acids

Allow selective admittance of Blue-Green and Red

light for Photosynthesis
Flavonoid Functions Con’t.
Reduces the palatability of plants or causes
herbivores to avoid the plants altogether
Affects interaction of plants with other
organisms: Inhibit or encourages bacteria and
mychorizzae associations
Have anti-oxidative effects, antimicrobial anti-
carcinogenic and cardio-protective
Various classes of Flavoniods: Anthocyanins,
Flavonols, Flavones, IsoFlavones
FLAVONOIDS

Plant Pigments
 PLANT PIGMENTS
Flavonoids and anthocyanins are conspicuous plant pigments in nature that
are responsible for the beauty and splendor of flowers, fruits, fruit tree blossoms
and of the autumn leaves.

Flavones are responsible for the yellow and orange colors; and the anthocyanins
are the source of red, violet and blue colors. These compounds occur mainly in
higher plants and are less common in the lower orders. You don’t find them in
algae, fungi or bacteria.

The flavonoids play a major role in attracting insects to feed and pollinate these
plants. Some of them also have a bitter taste and repel harmful insects like
caterpillars.

Flavonoids are thought to be antioxidants, and play a major role in our diet,
preventing the ravages of aging caused by free-radicals.

These compound have their biosynthetic origin in both the skimic acid pathway
and the acetogenin pathway - they are of hybrid origin.
Anthocyanins
Range in color from Red through Purple and Blue
Main constituents of plant flower color
Important in attracting pollinators and dispersers
Mutualistic relationships!
Flavonols and Flavones
Mostly colorless pigments in the leaves of plants
Control light admittance to leaves: photosynthesis
and UV protection
Cause of leaf color change in the Fall:
As Chlorophyll breaks down - large quantities of
flavonols are converted to anthocyanins!
IsoFlavones
Found mostly in Legumes (Fabaceae)
Allelopathy – herbivory defense, pathogen
defense!
Flavonoid Biosynthesis

Constructed from the products of two different pathways

And catalyzed by CHALCONE SYNTHASE
Flavonoid mempunyai kerangka dasar yang
terdiri dari 15 atom karbon, dua cincin benzen
(C6) terikat pada suatu rantai propan (C3) yang
dapat atau atau tidak dapat membentuk cincin
ketiga, sehingga membentuk suatu konfigurasi
C6-C3-C6.
Susunan dari senyawa tersebut dapat
menghasilkan tiga jenis struktur, yaitu 1,3-
diarilpropan (flavonoid), 1,2-diarilpropan
(isoflavonoid), dan 1,1-diarilpropan (neoflavonoid)
.
1,3-diarilpropan
(Flavonoid)
1,1-diarilpropan
(Neoflavonoid)

1,2-diarilpropan
(Isoflavonoid)
Senyawa flavonoid mempunyai kerangka 2-fenil
kroman. Posisi orto dari cincin A dan atom karbon
yang terikat dari cincin B dari 1,3-diaril propan
dihubungkan oleh jembatan oksigen sehingga
membentuk suatu cincin heterosiklik yang baru
(cincin C)

2-fenil kroman
Penyebaran Flavonoid pada Tumbuhan
Flavonoid terdapat pada semua jenis tanaman
terkecuali alga.
Flavonoid tersebar pada seluruh bagian tanaman
seperti pada daun, bunga, buah, biji, akar, kayu, kulit
kayu, tepung sari, batang dan getah batang.
Biasanya dijumpai pada vakuola dan beberapa
diantaranya terdapat dalam kromoplast dan kloroplast.
Flavonoid juga terdapat pada sayap kupu-kupu, sekresi
lebah (propolis) dan dalam kelenjar bau berang-berang.
Itupun dengan anggapan bahwa flavonoid tersebut
berasal dari tumbuh-tumbuhan yang menjadi makanan
bagi hewan tersebut dan tidak dibiosintesa di dalam
tubuh mereka
Tumbuhan yang secara taksonomi mempunyai
hubungan dekat, misalnya satu famili atau satu
suku cenderung menghasilkan flavonoid yang
sama.
Angiospermae merupakan tumbuhan yang
paling banyak mengandung flavonoid, kemudian
Gimnospermae, serta sedikit fungi dan paku.
Pada umumnya flavonoid terdapat dalam
tumbuhan terikat pada gula sebagai glikosida,
dalam satu tumbuhan mungkin saja terbentuk
beberapa kombinasi glikosida .
Biosintesa Flavonoid
jalur sikimat dan asetat malonat.
Flavonoid yang pertama terbentuk pada biosintesis
adalah kalkon dan bentuk isomernya flavon.
Selanjutnya akan diturunkan flavonoid-flavonoid lainnya.
Modifikasi flavonoid lebih lanjut akan terjadi pada
berbagai tahap berikutnya, terjadi penambahan atau
pengurangan hidroksilasi, metilasi gugus hidroksil atau
inti flavonoid, isoprenilasi gugus hidroksil atau inti
flavonoid, metilasi gugus orto dihidroksi, dimerisasi
(pembentukan biflavonoid, pembentukan bisulfat) dan
glikosilasi gugus hidroksil (pembentukan flavonoid 0-
glikosida) atau inti flavonoid (pembentukan flavonoid C-
glikosida)
Sifat Fisika dan Kimia Flavonoid

Flavonoid umumnya bersifat polar sehingga larut dalam

pelarut polar seperti etanol, metanol, butanol, aseton,
dimetilsulfoksida, dimetilformamida, air dan lain-lain.
Adanya gula yang terikat pada inti flavonoid
menyebabkan flavonoid glikosida lebih mudah larut
dalam air sehingga campuran pelarut organik diatas
dengan air merupakan pelarut yang baik untuk glikosida.
Sedangkan flavonoid yang berupa aglikon seperti
isoflavonoid, flavanon dan flavonol yang termetoksilasi
mudah larut dalam pelarut eter dan kloroform.
Pembagian Flavonoid

Aglikon Flavonoid
jenis aglikon flavonoid :khalkon, flavanon,
dihidrokhalkon, flavon, flavonol, auron, isoflavon,
dihidroflavanol, rotenoid, antosianidin dan (+) katekin.
 Khalkon dan auron mempunyai struktur dengan cincin
terbuka dan diberi penomoran yang berbeda dengan
flavonoid lainnya. Kalkon dan auron sedikit ditemui di
alam seperti halnya flavanon, leuko antosianidin.
Sedangkan flavonoid yang banyak ditemui di alam
adalah flavonol, flavon dan antosianidin
Flavonoid O-glikosida

 Dimana satu gugus hidroksil flavonoid atau lebih berikatan

dengan gugus karboksil dari gula dengan ikatan hemiasetal
yang tidak tahan asam.
 Gugus hidroksil pada setiap inti flavonoid dapat diglikosilasi, tapi
pada kenyataannya gugus hidroksil pada tempat tertentu lebih
mudah terglikosilasi dibandingkan dengan tempat yang lain,
seperti pada posisi 7 hidroksi pada flavon, isoflavon dan
dihidroflavon.
 Pengaruh glikosilasi menyebabkan flavonoid menjadi kurang
reaktif dan lebih mudah larut dalam air.
 Gula yang paling umum ditemukan : glukosa, galaktosa,
ramnosa, xilosa dan arabinosa. Disakarida : soforosa,
gentibiosa, rutinosa, neohesperidosa, kadang-kadang trisakarida
bahkan tetrasakarida (11).
Flavonoid C-glikosida

flavonoid dengan struktur yang khas, dimana

ikatan antara gula dengan aglikon adalah ikatan
karbon-karbon.
Jenis aglikon flavonoid yang dijumpai sangat
terbatas. Yang umum dijumpai adalah flavon C-
glikosida.
Jenis gula yang terikat antara lain glukosa,
galaktosa, rhamnosa, xilosa dan arabinosa.
Ikatan C-glikosida lebih tahan asam dibandingkan
dengan ikatan flavonoid 0-glikosida.
Flavonoid Sulfat

Flavonoid sulfat termasuk flavonoid yang mudah

larut dalam air. Senyawa ini mengandung satu ion
sulfat atau lebih yang terikat pada hidroksi fenol
atau gula.
Senyawa ini sebenarnya bisulfat karena terdapat
sebagai garam kalium yaitu flavon-0-SO3K.
Banyak yang berupa glikosida bisulfat dimana
bagian bisulfat terikat pada bagian hidroksi fenol
mana saja yang masih bebas atau pada gula.
Biflavonoid

Biflavonoid merupakan flavonoid dimer. Flavonoid

yang biasanya terikat adalah flavon dan flavanon
yang secara biosintesis mempunyai pola oksigenasi
yang sederhana pada 5,7,4’ atau kadang-kadang 5,7,
3,4’ dan ikatan antar flavonoid berupa ikatan karbon-
karbon atau ikatan eter.
Monomer flavonoid yang tergabung menjadi
flavonoid dapat berjenis sama atau berbeda dan
letak ikatannya berbeda.
Sifat fisika dan kimianya menyerupai sifat
monoflavonoid pembentuknya. Senyawa ini jarang
ditemukan dalam bentuk glikosida dan
penyebarannya terbatas terutama pada
Gymnospermae.
Aglikon Flavonoid Yang Optik Aktif

Flavonoid ini mempunyai atom karbon asimetrik

sehingga menunjukkan keaktifan optik.
Yang temasuk golongan flavonoid ini adalah
flavanon, dihidroflavanol, katekin, pterokarpan,
rotenoid dan beberapa biflavonoid.
Bioaktifitas Flavonoid
Bioaktivitas flavonoid pertamakali diungkapkan oleh Rusnyak dan
Szent-Gyorgyi pada tahun 1936. senyawa “citrin” yang diisolasi dari
jeruk lemon dapat menormalkan kembali resistensi pembuluh
kapiler yang menurun pada pasien “vascular purpura”.
Penulusuran melalui Natural Product Alert (Napralert)
menunjukkan flavonoid sebagai analgesik, diuretik, antikonvulsan,
antiinflamasi, antifertilitas, dan antitumor.
Kuersetin telah dilaporkan sebagai anti kanker dan antioksidan
serta pewarna tekstil. Disamping itu juga dapat digunakan sebagai
alternatif pencegahan diabetes mellitus dengan menghambat
kerja enzim aldosa reduktase dalam pembentukan sorbitol.
rutin sering digunakan untuk menyembuhkan beberapa penyakit
antara lain pendarahan selaput jala (retinal haemorrhange),
hipertensi, yang disebabkan naiknya fragilitas kapiler, pendarahan
yang bersifat keturunan seperti haemofilia dan pendarahan gusi.
Deteksi Flavonoid

Untuk mengetahui adanya senyawa flavonoid

dalam suatu tumbuhan dapat dilakukan sebagai
berikut, sampel segar sebanyak 4 gram dipotong
halus, dididihkan dalam 25 ml etanol selama 15
menit dan saring selagi panas.
Filtrat diuapkan di atas penangas air sampai
setengahnya, kemudian tambahkan asam klorida
pekat dan logam Mg, terbentuk warna kuning
sampai merah menandakan adanya flavonoid.
 shikimic acid
pathway OH
NARINGENIN
CoAS
A different starter found in grapefruit
O
than acetyl-CoA.
4-hidroksisinamoil-
CoA malonyl-CoA acetogenin
3x pathway

OH
OH
H
O SCoA
HO O :
O

O O OH O
Michael
internal Claisen addition
and enolizations
Chalkon OH

HO O

MIXED-ORIGIN A FLAVANON
COMPOUND
flavones are yellow OH O

or orange pigments
naringenin
Anthocyanin
Flower Pigments
Anthocyanin Leaf Pigments
Autumn Leaves

In Spring and Summer

chlorophyll (green) masks
the anthocyanin colors.
 ANTHOCYANIDINS AND ANTHOCYANINS
OH OH OH

HO O HO O HO O
R R R

O2
OH
NADPH OH

OH O OH O OH OH

naringenin (R=H)

[O]

OH OH

+ OH
HO O HO O
R R

OH OH
Anthocyanins are - 2 H2O
OH OH OH
red, violet or blue
pigments. pelargonidin (R=H)
cyanidin (R=OH)
plant flower and cyanidin is blue
ANTHOCYANIDINS
leaf pigments pelargonidin is pink
Flavonolignan
Kombinasi struktur flavonoid dan lignan
(Phenilpronoid/koniferil alkohol)
Contoh : Silibin (Silybum marianum)
Hepatoprotektor (antihepatotoksik), antioksidan
 (+ acetogenin piece)
Shikimate SHIKIMIC ACID
Pathways FLAVONOIDS

CHORISMIC ACID

PREPHENIC PHENYL-C3 ANTHRANILIC

ACID COMPOUNDS ACID

CINNAMIC
TYROSINE TRYPTOPHAN
ACIDS

PHENYLALANINE
PHENYL-C1
COMPOUNDS

ALKALOIDS ALKALOIDS ALKALOIDS

Pelajari hal 168 dst
Flavonoids and Stilbenes
Flavonoids and stilbenes are products from a
cinnamoyl-CoA starter unit, with chain extension
using three molecules of malonyl-CoA.
Stilbenes (e.g. resveratrol) or chalcones (e.g.
naringenin-chalcone) are the end-products formed
by enzymes stilbene synthase and chalcone
synthase respectively
Both structures nicely illustrate the different
characteristic oxygenation patterns in the two
aromatic rings derived from the acetate or
shikimate pathways
Flavonoids and Stilbenes
Though cyclizing the same substrate in different
ways,chalcone synthase and stilbene synthase
enzymes are found to share some 75–90% amino
acid sequency identity.
Whilst chalcone synthase enzymes appear to be
found in all plants, stilbene synthase activity has a
much more restricted distribution.
With the stilbenes, the terminal ester function is no
longer present; therefore, hydrolysis and
decarboxylation have also taken place during this
transformation.
Resveratrol (Stilbene)
a constituent of grapes and wine, as well as other
food products, with antioxidant, anti-inflammatory,
inhibition of platelet aggregation, and protective
activity against cancer and cardiovascular diseases
Commercial material is isolated from grapeskins or
Japanese knotweed (Polygonum cuspidatum, syn.
Fallopia japonica Polygonaceae)
Resveratrol also has an tifungal properties and is
formed as a phytoalexin in some plant species,
including grapes and peanuts, as a result of infection.
combretastatin A-4
Another natural stilbene of medicinal interest is combretastatin A-4,
isolated from bark of the tree Combreta caffrum (Solanaceae)
It is a potent cytotoxic agent which strongly inhibits polymerization
of tubulin by binding to the colchicine site.
The water-soluble phosphate pro-drug is currently showing
considerable promise in clinical trials against various solid tumours;
it appears to reduce blood flow in the tumour markedly.
Chalcones

act as precursors for a vast range of flavonoid

derivatives found throughout the plant kingdom.
Enzymic and genetic studies for this group of
compounds are now well advanced.
Most flavonoids contain a six-membered
heterocyclic ring, formed by Michael-type
nucleophilic attack of a phenol group onto the
unsaturated ketone to give a flavanone, e.g.
naringenin
Reaksi Modifikasi Falvonoid
Flavonoid isomerization can occur chemically, with
acid conditions favouring the flavanone and basic
conditions thechalcone.
In nature, however, the reaction is enzyme catalysed
and stereospecific, resulting in formation of a single
flavanone enantiomer.
Many flavonoid structures, e.g. liquiritigenin, have lost
one of the hydroxyl groups, so that the acetate-derived
aromatic ring has a resorcinol oxygenation pattern
rather than the phloroglucinol system.
This modification has been tracked down to the action
of a chalcone reductase enzyme concomitant with the
chalcone synthase; thus, isoliquiritigenin is produced
rather than naringenin-chalcone.
Reduction of the linear poly-β-ketoester or of the
cyclic trione might be formulated evidence points to
the cyclic trione as substrate.
The last stage(s) in chalcone formation through
enolization or dehydration/enolization are probably
spontaneous and non-enzymic.
Flavanones can then give rise to many variants on
this basic skeleton, e.g. flavones, flavonols,
anthocyanidins, and catechins (Figure 4.43).
Most of the enzyme systems show rather broad
substrate specificity and convert compounds with
different oxygenation patterns in the aryl substituent.
Modifications to the hydroxylation patterns in either
of the two aromatic rings may occur, generally at the
flavanone or dihydroflavonol stage, and methylation,
glycosylation, and dimethylallylation are also
possible, increasing the range of compounds
enormously.
A high proportion of flavonoids occur naturally as
water-soluble glycosides.
Manfaat Flavonoid
some flavonoids are particularly beneficial, acting
as antioxidants and giving protection against
cardiovascular disease, certain forms of cancer,
and, it is claimed, age-related degeneration of cell
components.
Their polyphenolic nature enables them to
scavenge injurious radicals such as superoxide
and hydroxyl radicals.
Quercetin in particular is almost always present in
substantial amounts in plant tissues; it is a powerful
antioxidant, chelating metals, scavenging radicals,
and preventing oxidation of low density lipoprotein.
Flavonoids in red wine (quercetin, kaempferol, and
anthocyanidins) and in tea (catechins and catechin
gallate esters) are also demonstrated to be effective
antioxidants.
Green tea contains epigallocatechin gallate (Figure
4.44), a particularly effective agent.
Flavonoids contribute to plant colours: yellows
from chalcones and flavonols, and reds, blues, and
violets from anthocyanidins.
Even the colourless materials, e.g. flavones,
absorb strongly in the UV and are detectable by
insects, probably aiding flower pollination.
Catechins form small polymers (oligomers), the
condensed tannins, e.g. the epicatechin trimer
(Figure 4.44), which contribute astringency to our
foods and drinks, as do the simpler gallotannins
(see page 138), and are commercially important
for tanning leather.
Theaflavins, antioxidants found in fermented tea
(see page 415), are dimeric catechin structures in
which oxidative processes have led to formation
of a seven-membered tropolone ring.
The flavonol glycoside rutin (Figure 4.45) from
buckwheat (Fagopyrum esculentum;
Polygonaceae) and rue (Ruta graveolens;
Rutaceae)
The flavanone glycoside hesperidin from Citrus
peels have been included in dietary supplements
as vitamin P and claimed to be of benefit in
treating conditions characterized by capillary
bleeding; their therapeutic efficacy is far from
conclusive.
Neohesperidin (Figure 4.45) from bitter orange
(Citrus aurantium; Rutaceae) and naringin from
grapefruit peel (Citrus paradisi) are intensely bitter
flavanone glycosides
It has been found that conversion of these
compounds into dihydrochalcones by hydrogenation
in alkaline solution (Figure 4.46) producesa
remarkable change to their taste, and the products
are now intensely sweet, being some 300–1000
times as sweet as sucrose.
Neohesperidin-dihydrochalcone is used as a non-
sugar sweetening agent
Penentuan Kadar (DAB 10)
Flavonolignans
An interesting combination of flavonoid and
lignan-like structures is found in a group of
compounds called flavonolignans.
They arise by oxidative coupling processes
between a flavonoid and a phenylpropanoid, the
latter usually coniferyl alcohol. Thus, the
dihydroflavonol taxifolin (dihydroquercetin)
through one-electron oxidation may provide a
radical, which may combine with the radical
generated from coniferyl alcohol (Figure 4.47).
Silybin, found in Silybum marianum (Compositae/
Asteraceae) as a mixture of two trans
diastereoisomers, silybins A and B, reflecting a
lack of stereospecificity for the original radical
coupling
The flavonolignans from Silybum (milk thistle)
have valuable antihepatotoxic properties and can
provide protection against liver-damaging agents
[Box 4.7]
Coumarinolignans are products arising by a
similar oxidative coupling mechanism which
combines a coumarin with a cinnamyl alcohol and
may be found in other plant
Stilbenolignans are also known; these combine a
stilbene such as resveratrol (page 169) with a
cinnamyl alcohol
Isoflavonoids
The isoflavonoids form a quite distinct subclass
of flavonoid compound, being structural variants
in which the shikimate-derived aromatic ring has
migrated to the adjacent carbon of the heterocycle.
This rearrangement process is brought about by a
cytochrome P-450-dependent enzyme requiring
NADPH and O2 cofactors, which transforms the
flavanones liquiritigenin or naringenin into the
isoflavones daidzein or genistein respectively via
intermediate hydroxyisoflavanones (Figure 4.49).
A involves methylation at the hydroxyisoflavanone
stage; the dehydratase enzymes appear to be specific
for either hydroxy or methoxy substrates.
The rearrangement step is quite rare in nature, and
although flavonoids are found throughout the plant
kingdom, isoflavonoids are almost entirely restricted to
the Leguminosae/Fabaceae plant family.
many hundreds of different
isoflavonoids have been identified, and structural
complexity is brought about by hydroxylation and
alkylation reactions, varying the oxidation level of the
heterocyclic ring, or forming additional heterocyclic
ring
Pterocarpans, e.g. medicarpin from lucerne
(Medicago sativa) and pisatin from pea (Pisum
sativum), and isoflavans, e.g. vestitol from lucerne,
have antifungal activity and form part of the natural
defence mechanism against fungal attack in these
plants.
Simple isoflavones (such as daidzein) and
coumestans (such as coumestrol) from lucerne and
clovers (Trifolium species) have sufficient
oestrogenic activity to affect the reproduction of
grazing animals seriously and are termed phyto-
oestrogens [Box 4.8].
These planar molecules undoubtedly mimic the
shape and polarity of the steroid hormone estradiol
(see page 291).
Isoflavonoids in the human diet, e.g. from soya
(Glycine max) products, are believed to give some
protection against oestrogen-dependent cancers
such as breast cancer, by restricting the
availability of the natural hormone.
In addition, they are employed as dietary
oestrogen supplements for the reduction of
menopausal symptoms, in a similar way to
hormone replacement therapy (HRT; see page 294)
.
Rotenoids
The rotenoids take their name from the first known example
rotenone, and are formed by ring cyclization of a
methoxyisoflavone (Figure 4.51).
Rotenone itself contains a C5 isoprene unit (as do virtually all the
natural rotenoids) introduced via dimethylallylation of
demethylmunduserone.
The isopropenylfurano system of rotenone and the dimethylpyrano
of deguelin are formed via rotenonic acid (Figure 4.51) without any
detectable epoxide or hydroxy intermediates (compare
furocoumarinspage 164). Rotenone and other rotenoids are
powerful insecticidal and piscicidal (fish poison) agents, interfering
with oxidative phosphorylation.
They are relatively harmless to mammals unless they enter the
bloodstream, being metabolized rapidly upon ingestion.