Secondary metabolites

are derived from

primary metabolites

Why secondary metabolites?

Chemical warfare to protect plants from the attacks by predators,
pathogens, or competitors
Attract pollinators or seed dispersal agents
Medicine
Industrial additives
Possibly over 250,000 secondary metabolites in plants
Classified based on common biosynthetic pathways where a
chemical is derived.
Four major classes: Alkaloids, glycosides, phenolics, terpenoids
2

Alkaloids

Most are derived from a few

common amino acids (i.e.,
tyrosine, tryptophan, ornithine
or argenine, and lysine)
Compounds have a ring
structure and a nitrogen
residue.
Indole alkaloids is the largest
group in this family, derived
from tryptophan
Widely used as medicine

Phenolics

Derived from aromatic amino acids, such

as phenylalanine, tyrosin, and trytophan.
All contain structures derived from phenol
Some examples:
Coumarins: antimicrobial agents, feeding
deterrents, and germination inhibitors.
Lignin: abundant in secondary cell wall,
rigid and resistant to extraction or many
degradation reagents.

Terpenoids

Terpenes are generally polymers

of 5-carbon unit called isoprene

Give scent, flavors, colors,

medicine...

Glycosides

Compounds that contain a

carbonhydrate and a noncarbohydrate
(glycon and aglycon)

Three plant hormones are

derived from the terpenoid
pathway.

Glucosinolates: found primarily in the

mustard family to give the pungent
taste.
4

KISI-KISI : TOPIK TERPENOID

Pengertian dan Kerangka terpenoid

Kondensasi/pembentukan terpenoid dari unit-unit isopren

Jalur biosintesis terpenoid
Struktur dasar, acyclic (open chain) dan cyclic (monocyclic; bicyclic,
tricyclic, etc)
Contoh-contoh senyawa, dan khasiat farmakologi dari : hemiterpenoid,
monoterpenoid, diterpenoid, triterpenoid, tetraterpenoid, dan
politerpenoid.

Pengertian minyak atsiri, contoh, struktur, sumber, dan cara ekstraksi

Triterpen steroid glikosida

Terpenoid
C-5: Hemiterpenes
C-10: Monoterpenes
C-15: Sesquiterpenes

Hemiterpen (C5 )

C-20: Diterpenes
C-25: Sesterterpenes
C-30: Triterpenes

- Terpenoid yang mempunyai 5 karbon.

- Jarang ditemukan
- Senyawa volatil
Iso-amilalkohol (ester m.atsiri Mentha & Eucalyptus).
Asam isovalerat (Valeriana sp.)
Asam tiglat (Geranium sp.)

Head to tail
Tail to tail

Terpenoide Natural Products

NH2

3 ATP

HO

OH
HO

(C-5)

Rearrange

O
O
O
HO P O P O P O
OH OH OH

Isopentenylpyrophosphate

Mevalonate
(C-6)

O
HO

OH

ATP, Adenosine-5'-triphosphate

Isopentenylpyrophosphate

Dimethylallylpyrophosphate

trans-Geranylpyrophosphate

(C-5)

(C-5)

(C-10)

Monoterpenes (C-10)
Ex.
OH

Geraniol

(+) Limonene

Monoterpenes

Voilatile compds, smell, taste etc.

OH

Acyclic

OH

OH

OH

HO
OH

trans-Geraniol

(-)-citronellol

(-) Linalool

-Pinene

(+) Camphor

-Pinene

Pyrethrines
Insecticides from Chrysanthemum cinerariifolium

(+)--Terpineol

(-)-Menthol

Monocyclic
Bicyclic
Tricyclic
Tetracyclic
The Chiral
Pool
Pentacyclic

R'

Thymol

(+)-Carvone

Cyclic

Cannabinoids,
from Cannabis sativa (Hemp)

R
O
O

C-10

OH

C-10

O
O

Permetrin, Nix

Cl
O
Cl

Shampoo, Lice, scabies

Synth. analog
more stable
mixt of isomers

Tetrahydrocanabinol

OH

H
O

Nabilone
Antiemetic (not reg N.)

Monoterpenes & Sesquiterpenes

Monoterpenes: 10 carbons
Sesquiterpenes: 15 carbons
7
1

14

15
5

13

3
2

10

Menthol

Nerolidol

10

12

11

Antiseptic Monoterpenes
Cineole (1,8-cineole or eucalyptol) is the major constituent of
Eucalyptus oil (~ 70 85%)*
Antiseptic, antibacterial, expectorant
-Pinene, a minor constituent (up to 14%) is toxic in very high doses

Cineole

-Pinene

Seskiterpen (C15)
- Penambahan unit C5 isopentenil piropospat (IPP) pd geranil piroposopat
(GPP) adl. pemanjangan reaksi fenil transferase yang menghasilkan
prekursor seskiterpen, farnesil piro pospat (FPP).
- FPP seskiterpen linear & siklik.
- Panjang rantai naik, jumlah siklisasi naik.
- Siklisasi dan karbokation meningkatkan variasi derivat
- Kurang volatil dibanding mono- Bisabolene dan zingiberen: aroma ( Zingiber officinale)
- Parthenolide: antimigren (Tanacetum partenium)
Contoh2 Seskiterpen (C15) - -Santonin : antelmintik (Artemisia sp.)
- Tapsigargin : pengendali tumor (Thapsia garganica)
- Elepantopin: sitotoksik (Elepanthopus elatus)
- Partenin: alergi kulit (Partenium hysterosphorus)

Contoh2 Seskiterpen (C15)

Artemisinin (Qinghaosu)
- Isolasi dari Artemisia annua (qinghao)
- Artemisinin sebagai antimalaria yg sifatnya blood schizontocide & tidak
toksik.
- Seskiterpen lakton mempunyai ikatan peroksida yang unik
- Pada tanaman Artemisia annua ditemukan:
0,05-0,2% artemisinin
0,01% artemisiten
0,2-0,8% asam artemisinat.

Diterpenes (C-20)
P

Isopentenylpyrophosphate
(C-5)
O P
P

Isopentenylpyrophosphate
(C-5)
O P
P

trans, trans-Farnesylpyrophosphate
(C-15)

trans-Geranylpyrophosphate
(C-10)

Head to tail coupling

Sesquiterpenes
O

all trans-Geranylgeranylpyrophosphate
(C-20)
HO

Diterpenes

Phytol

Vitamine K1

N
N Mg N

C-20
HO

O
Vitaminee E (-Tocopherol)

O
H
CO2Me
H

Chlorophyll A

DITERPENES (C20)

The diterpenes arise from geranylgeranyl diphosphate (GGPP), which is

formed by addition of a further IPP molecule to farnesyl diphosphate
One of the simplest and the most important of diterpenes is phytol, a
reduced forms the lipophilic side-chain of the chlorophylls, e.g. chlorophyll a
A phytyl substituent is also found in vitamin K1 (phylloquinone)

 Cyclization reactions of GGPP mediated by carbocation formation, plus the potential for
Wagner-Meerwein rearrangements, will allow many stuctural variants of diterpenoids to
be produced
Taxol (Taxus brevifolia); an important new anticancer agent
the side chain containing aromatic rings are derived from shikimate via phenylalanine.

trans, trans-Farnesylpyrophosphate
(C-15)

Triterpenes (C-30)
Steroid

tail to tail coupling

Squalene (C-30)

Enzyme-Nu

Enz--Nu

Squalene
epoxide
cyclase B

Squalene
epoxidase

HO
HO

Lanosterol

(Animals)

Stereoids
Enz--Nu

H
HO

HO

Cycloartenol

(Plants)

Triterpenes C30

Instead, two molecules of FPP are joined tail to tail to yield the
hydrocarbon squalene
During the coupling process, removal of the diphospat groups, a proton
from a C-1 position of one molecule of FPP is lost and proton from
NADPH is inserted
Several seed oils as quite rich sources of squalene, e.g. Amaranthaceae
To form squalene, C-1 of the two FPP unit must eventually be coupled,
whilst presqualene PP formation has actually joined C-1 of one
molecule to C-2 of the other

Cyclization of sequalene is via the intermediate squalene-2,3-oxide.

Produced in a reaction catalysed by a flavoprotein requiring O2 and
NADPH cofactors.
The cyclization are carbocation mediated and proceed in a step-wise
sequence
lanosterol

Triterpenes & Steroids

~ 4,000 different structures known
Triterpenes have 3 x 10 = 30
carbons
Steroids are derived from them; lose
3 carbons to end up with 27
Triterpenes
Saponins
Triterpenoid
Steroidal
Steroids
Misc. steroids
Phytosterols
Cardiac glycosides

Triterpene skeleton

Steroid skeleton

Cardiac Glycosides in Lily of the Valley

~ 40 different glycosides based on
several different aglycones; variable
Convallatoxin highly active, but
generally no more than 10% of the
amount ingested can be absorbed
Positive inotropic effect; used for
mild cardiac insufficiency

Tetraterpenes: Carotenes & Xanthophylls

Lycopene parent compound of carotenoids
Carotenes alpha-, beta-, delta- & gamma-carotenes
are closely related
Xanthophylls carotenoids with oxygen in their
structures include lutein, neoxanthin & violaxanthin;
capsanthin & capsorubin; astaxanthin

Stereoids

12

13

11
1

20 steps
2

H
H
HO

Lanosterol
(C-30)

HO

Cholesterol
(C-27)

3
4

10

17
D

16

14 15

17

17

Cholesterol

Sex hormones
Estrogens
Progesterones
Testosteron and anabolic stereoids
Corticoids
Glucocorticostereoids
Cortison etc. etc.
Mineralcorticostereoidsr
Aldosterone

B / C og C / D always trans (animals)

A / B trans fused

A / B cis fused

Digitalis glycosides
Fucidinic acid (antibiotic)
Brassinostereoids (Plant growth hormones)
etc. etc.

10

10

5
5

Sex hormones - Progesterones (gestagenes, progestrines)

HO

O
H
H

Many semisynth drugs in use (better bioavalabil.)

Metabolism

H
H

HO

Progesterone
OH
H
H

OH

Testosterone

5-reduktase

H
O

Testosterone

5-Dihydrotestosterone (5DHT)
More active A-B ring trans
Cis isomer inaktive
OH

OH
H

Doping - Anabolic stereoids

H
OH

OH
H

Testosterone

Epi-testosteron
Only small androgene / anabole activity
Different biosynt. pathway than T

THG (tetrahydrogestrinon)

Gestrinon

Normal: T : E ratio ca 6 : 1
Doping T: E increases
E added to hide signs of doping

Corticostereoids
Mineralcorticoid
OH O

Aldosterone
Regulation of elektrolyttic ballance
increase re-uptake of Na (and hence H20)

OH

O
H
H

Glucocorticoid Effect on metabolism (karbohydrates, lipids, proteins)

OH

Antiinflammatoric

OH

HO
H
H

Numerous semisynth. analogs as drugs

Various antiinflam. activity, mineralcorticoid side effects

Hydrokortison
O

Risopus
nigricans

H
H
O

HO
H
O

Oks

Progesteron

H
O

OH

HO

HO

NaBH4

H
O

OH

Hydrokortison

Digitalis glycosides (cardenolides)

-Treatment of hart disease 1500 BC (Egypt)
-Increase hart contraction
-Tox.
Aglycone: Biolog. activity
O
O

(KH part; solubility etc..)

R
-lactone

H
H
(Digitoxose)3 O

CH3

OH

H
OH
OH

OH

-D-digitoxose

Digitoxin
Digitoxin R= H
Digoxin
Lanoxin R= OH

A-B and C-D cis condens.

A-B cis, B-C trans. C-D cis

All trans

Digitalis purpurea
(foxglowe, revebjelle)

R
R

H
H

R
H

Stability
Acid: Cleavage of sugars (acidic hydro acetals)
Base:
O
O

HO

R O

HO

OH

OH

Double bond
migr,

enol

taut.
OH

HO O

OH

H
H

OH

OH

Aldehyde

Hemiacetale

Acetale

SESTERTERPENES (C25)
The most common type of marine sesterterpenoid is exemplified by
scalarin and this structure can be envisaged as the result of a concerted
cyclization sequence

 are represented by only one group of compounds, the carotenoids

These compounds play a role in photosynthesis, but also found in nonphotosintesis plant tissues, in fungi and bacteria.
Formation of the tetraterpene skeleton, e.g Phytoene, involves tail-to-tail
coupling of two molecules of GGPP
For squalene formation, the allylic cation accepts a hydride ion from NADPH,
but for phytone biosynthesis, a proton is lost.
Conjugation is extended then by a squence of desaturation reaction,
removing pairs of hydrogens alternately from each side of the triene system
lycopene

Vitamin A1 (retinol), derived in mammals by oxidative metabolism

of a tetraterpenoid mainly -carotene, is catalysed by an O2dependent dioxygenase, probably via an intermediate peroxide

Meroterpenoids netural products of mixed biosynthetic origin

that are constructed from isoprene and nonisoprenoid units
Example : ergot alkaloid alkaloid contain isoprene unit
Quinine alkaloid & monoterpenoid unit

Glikosida flavonol

Glikosida saponin

 Glikosida adalah senyawa yang terdiri atas gabungan dua bagian senyawa,
yaitu gula dan bukan gula.
Keduanya dihubungkan oleh suatu bentuk ikatan berupa jembatan
oksigen (O glikosida, dioscin), jembatan nitrogen (N-glikosida,
adenosine), jembatan sulfur (S-glikosida, sinigrin), maupun jembatan
karbon (C-glikosida, barbaloin).

Bagian gula biasa disebut glikon sedangkan bagian bukan gula disebut
sebagai aglikon atau genin.
Apabila glikon dan aglikon saling terikat maka senyawa ini disebut sebagai
glikosida. Glikosida berbentuk kristal atau amorf. Umumnya mudah larut
dalam air atau etanol encer (kecuali pada glikosida resin).
Glikosida diklasifikasikan berdasarkan macam aglikon yang dihubungkan
dengan efek farmakologisnya.

Kerugian dari klasifikasi seperti ini adalah banyak senyawa lain yang lebih
spesifik yang juga mempunyai efek terapi.
Pengklasifikasian tidak dilakukan secara farmakologis karena banyak jenis
glikosida yang mempunyai efek terapeutik yang sama.

Penggolongan glikosida berdasarkan aglikonnya adalah sebagai berikut.

1. Glikosida Sterol-Cardio Active : Digitalis
2. Glikosida Antrakinon : Aloe, Casia Acutifolia
3. Glikosida Saponin : Saponin
4. Glikosida Sianofor : Prunus amygdalus
5. Glikosida Thosianat : Mustard, Brassica nigra
6. Glikosida Flavonol : Ruta Graviolens
7. Glikosida Alkohol : Salix Purpurea, S. Fragilis
8. Glikosida Aldehid : Vanili
9. Glikosida Lakton : Kumarin: Tonka, Cantharides
10. Glikosida Fenol
11. Glikosida yang Aglikonnya tidak dapat dimasukkan dalam golongan di atas