TerpenoidsDr. Amol Kharat

Objectives

• To study the Terpenoids in the form of

�Meaning,

�Different types

�Properties, occurrences, uses�Properties, occurrences, uses

� Isolation Method

�General Biogenetic Pathway

�Pharmacognostic account of different drug con

taining important constituents Terpenoids.

INTRODUCTION

Terpenoids are the secondary metabolites

synthesized by plants, marine organisms

and fungi by head to tail joining of isoprene

units. They are also found to occur in rocks,units. They are also found to occur in rocks,

fossils and animal kingdom.

Isoprene

The terpenoids, sometimes referred to as isoprenoids, are

a large and diverse class of naturally-occurring organic

chemicals similar to terpenes, derived from five-carbon

isoprene units assembled and modified in thousands of ways.isoprene units assembled and modified in thousands of ways.

Most are multicyclic structures that differ from one another

not only in functional groups but also in their basic carbon

skeletons. These lipids can be found in all classes of living

things, and are the largest group of natural products.

CALASSFICATION

TYPE OF NUMBER OF ISOPRENE

TERPENOIDS CARBON ATOMS UNITS

hemiterpene

monoterpenoid

sesquiterpenoid

C5

C10

C

one

two

threesesquiterpenoid

diterpenoid

triterpenoid

tetraterpenoid

C15

C20

C30

C40

three

four

six

eight

hemi = half di = two

sesqui = one and a half tri = three

tetra = four

NOTE

:

sesterterpenoid C25 five

Mnonoterpenoids

Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16.

Monoterpenes may be linear (acyclic) or contain rings. Monoterpenes may be linear (acyclic) or contain rings. Biochemical modifications such as oxidation or rearrange-ment produce the related monoterpenoids.

Mnonoterpenoids

Acyclic monoterpenoid:

C H 2 O H

C H O

Bicyclic monoterpenoid

¦Â-m y r c e n en e ro l g er a n ia l

Monocyclic monoterpenodi

OH

l-menthol menthone

O

cin eo le

O

¦Á---- ppppi nene

d-borneol

OH

Acyclic monoterpenoid

Acyclic monoterpenoid

Biosynthetically, isopentenyl pyrophosphate(异戊烯焦磷酸) and dimethylallyl pyrophosphate (二甲基丙烯焦磷酸酯) are combined to form geranyl pyrophosphate (牻牛儿醇焦磷酸酯).

Geranyl pyrophosphate

Acyclic monoterpenoid

Elimination of the pyrophosphate group leads to the formation of acyclic monoterpenes such as ocimene and the myrcenes.

Myrcene (月桂月桂月桂月桂烯烯烯烯)

Acyclic monoterpenoid

Hydrolysis of the phosphate groups leads to the prototypical acyclic monoterpenoid geraniol.

geraniol（（（（香叶醇香叶醇香叶醇香叶醇））））

Acyclic monoterpenoid

Additional rearrangements and oxidations provide compounds such as citral (柠檬醛), citronellal(香茅香茅香茅香茅醛醛醛醛), citronellol(香茅醇), and many others.

citral（（（（柠檬醛）柠檬醛）柠檬醛）柠檬醛）

Acyclic monoterpenoid

Many monoterpenes found in marine organisms are halogenated(卤代的卤代的卤代的卤代的), such as halomon.

Halomon is a polyhalogenated monoterpene first isolated from the marine red algae Portieria the marine red algae Portieria

hornemannii.

It has attracted research interest because of its promising profile of selective cytotoxicity (细胞毒) that suggests its potential use as an antitumor agent.

Halomon

Monocyclic monoterpenoid

In addition to linear attachments, the isoprene units can make connections to form rings. The most common ring size in monoterpenes is a six-membered ring.

A classic example is the cyclization of geranyl pyrophosphate to form limonene (柠檬烯）柠檬烯）柠檬烯）柠檬烯）.pyrophosphate to form limonene (柠檬烯）柠檬烯）柠檬烯）柠檬烯）.

Monocyclic monoterpenoid

The terpinenes, phellandrenes(水芹水芹水芹水芹烯烯烯烯), and terpinolene(异松油异松油异松油异松油烯烯烯烯) are formed similarly. Hydroxylation of any of these compounds followed by dehydration can lead to the aromatic p-cymene(百里香素百里香素百里香素百里香素).

Important terpenoids derived from monocyclic terpenes are menthol (薄荷醇薄荷醇薄荷醇薄荷醇), thymol(麝香草酚麝香草酚麝香草酚麝香草酚,百里酚百里酚百里酚百里酚), carvacrol(香芹酚香芹酚香芹酚香芹酚,甲基异甲基异甲基异甲基异

丙基苯酚丙基苯酚丙基苯酚丙基苯酚) and many others.丙基苯酚丙基苯酚丙基苯酚丙基苯酚) and many others.

β-phellandrene p-cymene menthol

• waxy / crystalline substance

• clear or white

• solid at room temperature and melts slightly above.

Menthol

slightly above.

The main form of menthol occurring in nature is (-) - menthol, which is assigned the (1R, 2S, 5R) configuration.

(-) dextro- (+) laeotro-

a colourless liquid at room temperatures

with an extremely strong smell of oranges. Limonene

a chiral molecule (asymmetric carbon atoms)

is common with such formsis common with such forms

biological sources produce one enantiomer(对映体)

Limonene is common in cosmetic products. As the main odor constituent of citrus, D - limonene is used in food manufacturing and some medicines, e.g., bitter alkaloids, as a flavoring; it is also used as botanical insecticide

Be increasingly used as a solvent for cleaning purposes, such as the removal of oil from machine parts, as it is produced from a renewable source (citrus oil, as a byproduct of orange juice manu-facture).

Combustible, be considered as a biofuel

Limonene

Combustible, be considered as a biofuel

Limonene is common in cosmetic products. As the main odor constituent of citrus, D - limonene is used in food manufacturing and some medicines, e.g., bitter alkaloids, as a flavoring; it is also used as botanical insecticide

Chemistry

relatively stable, can be distilled without decom-position

oxidises easily in moist air to carveol and carvone

Limonene

oxidises easily in moist air to carveol and carvone

Dehydration with sulfur gives to p-cymene, hydrogen sulfide, as well as some sulfides.

Carvone (香芹酮)

Safety

limonene and its oxidation products are skin and respiratory irritants.

Although once thought to cause renal (肾脏的) cancer in rats, limonene now is considered by some

Limonene

cancer in rats, limonene now is considered by some researchers to be a significant chemopreventive agent with potential value as a dietary anticancer tool in humans.

Bicyclic monoterpenoid

Bicyclic monoterpenoid

Geranyl pyrophosphate can also undergo two sequential cyclization reactions to form bicyclic monoterpenes, such as pinene(蒎烯蒎烯蒎烯蒎烯) which is the primary constituent of pine resin.resin.

Bicyclic monoterpenoid

Other bicyclic monoterpenes include carene (蒈烯蒈烯蒈烯蒈烯) and camphene (樟樟樟樟脑萜脑萜脑萜脑萜).

Camphor(樟樟樟樟脑脑脑脑), borneol(龙脑龙脑龙脑龙脑) and eucalyptol(桉叶素桉叶素桉叶素桉叶素) are examples of bicyclic monoterpenoids containing ketone, alcohol, and ether functional groups, respectively. alcohol, and ether functional groups, respectively.

carene (蒈烯蒈烯蒈烯蒈烯)

camphor(樟樟樟樟脑脑脑脑) borneol(龙脑龙脑龙脑龙脑)

Bicyclic monoterpenoid

Role in Climate

Monoterpenes are emitted by forests and form aerosols

(气溶胶) that can serve as cloud condensation nuclei (CCN).

Such aerosols can increase the brightness of clouds and

cool the climate.

There are two structural isomers found in nature: α-pinene and β-pinene.

As the name suggests, both forms are important constituents of pine resin;

they are also found in the resins of many other

Pinene

they are also found in the resins of many other conifers, and more widely in other plants.

Both are also used by many insects in their chemical communication system.

Usage

Selective oxidation of pinene with some catalysts in chemical industry give many components for pharmacy, artificial odorants and so on. The primary oxidation product is verbenone(马鞭草烯酮马鞭草烯酮马鞭草烯酮马鞭草烯酮) .

Pinene

ry oxidation product is verbenone(马鞭草烯酮马鞭草烯酮马鞭草烯酮马鞭草烯酮) .

It can form by simple air oxidation but a synthetic method employs lead tetraacetate.

Eucalyptol

a natural colorless liquid

has a variety of synonyms

the dominant portion of "Eucalyptus oil“

comprises up to 90 percent of Eucalyptus oilcomprises up to 90 percent of Eucalyptus oil

Although it can be used internally as a flavoring and medi-

cine ingredient at very low doses, typical of many essential oils

(volatile oils), eucalyptol is toxic if ingested at high doses.

Uses of eucalyptol

flavorings, fragrances, and cosmetics.

an ingredient of mouthwash and cough suppressant.

reducing inflammation and painEucalyptol suppository(栓栓栓栓剂剂剂剂), reducing inflammation and pain

kill leukaemia cells in vitro

Eucalyptol suppository(栓栓栓栓剂剂剂剂),for the treatment of somerespiratory ailments

In a 1994 report released by five top cigarette companies, eucalyptol was listed as one of the 599 additives (添加添加添加添加剂剂剂剂) to cigarettes. It is added to improve the flavor.

Sesquiterpenoids

Sesquiterpenoids

Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be acyclic or contain rings, sesquiterpenes may be acyclic or contain rings, including many unique combinations.

Biochemical modifications such as oxida-tion or rearrangement produce the related sesquiterpenoids.

Sesquiterpenoids

• Acyclic sesquiterpenoids • Monocyclic sesquiterpenoids

O

¦Á- fa r n e s e n e¦Â- fa r n e s e n e

姜 稀 姜 黄 酮• Bicyclic sesquiterpenoids

O H

¦Á- eudesmolH

H

cadineneguaiazulene

Acyclic Sesquiterpenoids

When geranyl pyrophosphate reacts with isopentenyl pyro-phosphate, the result is the 15-carbon farnesyl pyrophosphate(焦磷酸法尼焦磷酸法尼焦磷酸法尼焦磷酸法尼酯酯酯酯) , which is an intermediate in the biosynthesis of sesquiterpenes such as farnesene(金合金合金合金合欢烯欢烯欢烯欢烯) . Oxidation can then provide sesquiterpenoids such as farnesol(金合金合金合金合欢醇欢醇欢醇欢醇) . then provide sesquiterpenoids such as farnesol(金合金合金合金合欢醇欢醇欢醇欢醇) .

Sesquiterpenes are found naturally in plants as defensive agents.

farnesyl pyrophosphate

farnesene

farnesol

Monocyclic Sesquiterpenoids

With the increased chain length and additional double bond, the number of possible ways that cyclization can occur is also increased, and there exists a wide variety of cyclic sesquiterpenes. In addition to common six-membered ring systems such as is found in zingiberene(姜姜姜姜烯烯烯烯), a consitituent of the oil from ginger, cund in zingiberene(姜姜姜姜烯烯烯烯), a consitituent of the oil from ginger, cyclization of one end of the chain to the other end can lead to macrocyclic(大大大大环的环的环的环的)rings such as humulene(葎草葎草葎草葎草烯烯烯烯) .

姜 稀zingiberene

Bicyclic Sesquiterpenoids

In addition to common six-membered rings such as in the cadinenes (杜松杜松杜松杜松烯烯烯烯), one classic bicyclic sesquiterpene is caryophyllene(丁香丁香丁香丁香烯烯烯烯), from the oil of cloves(丁香丁香丁香丁香), which has a nine-membered ring and cyclobutane (环丁烷环丁烷环丁烷环丁烷) ring. Additional unsaturation provides aromatic bicyclic sesquiter- pedditional unsaturation provides aromatic bicyclic sesquiter- penoids such as guaiazulene（（（（愈愈愈愈创木烷）创木烷）创木烷）创木烷）.

guaiazulene

H

H

cadinenecaryophyllene

Tricyclic Sesquiterpenoids

With the addition of a third ring, the possible structures become increasingly varied. Examples include longifolene(长松叶烯长松叶烯长松叶烯长松叶烯), copaene(胡椒胡椒胡椒胡椒烯烯烯烯)and the alcohol patchoulol.

longifolene copaeneisomers of

patchoulol

Example of Sesquiterpenoids

• Zingiberene

• is a monocyclic sesquitepenoid which

is the predominant constituent of the

oil of ginger (Zingiber officinale), from

which it gets its name.which it gets its name.

• Zingiberene Chemical name 5-(1,5-dim--ethyl-4-hexenyl)-2-methyl-1,3-cyclohexadieneChemical formulaC15H24

姜 稀zingiberene

Example of Sesquiterpenoids

used to treat multi-drug resistant strains of falciparum malaria(恶性恶性恶性恶性疟疟疟疟) .

isolated from the plant Artemisia

Artemisinin(Qing hao su)

isolated from the plant Artemisia annua.

Not all plants of this species con-tain artemisinin.

can be synthesized from artemisi-nic acid

Example of Sesquiterpenoids

History

Artemisia has been used by Chinese

herbalists for more than a thousand years in the treatment of many illnesses, such as skin diseases and malaria. The earliest

Artemisinin

skin diseases and malaria. The earliest record dates back to 200 BC , in the "Fifty two Prescriptions" unearthed from the Mawangdui Han Dynasty Tombs. Its anti-malarial application was first described in Zhouhou Beji Fang ("The Handbook of Prescriptions for Emergencies"), edited in the middle of fourth century by Ge Hong. 《肘后备急方》

Example of Sesquiterpenoids

In the 1960s a research program was set up by the Chinese army to find an adequate treatment for malaria.

In 1972, discovered artemisinin in the leav

Artemisinin

In 1972, discovered artemisinin in the leaves of Artemisia annua

It was one of 200 candidates tested for treating malaria and was the only one that was effective

Example of Sesquiterpenoids

it was found that it cleared malaria parasites from their bodies faster than any other drug in history.

Artemisinin

any other drug in history.

Artemisia annua is a common herb and has been found in many parts of the world, including along the Potomac River, in Washington, D.C.

Example of Sesquiterpenoids

Cancer treatment

is under early research and testing

peroxide lactone group

Artemisinin

peroxide comes into contact with high iron concentrations (common in cancerous cells), the molecule becomes unstable and releases reactive oxygen species.It has been shown to reduce angio-genesis (血管生成的血管生成的血管生成的血管生成的) and the expression ofvascular endothelial growth factor(血管内皮生长因子)in some tissue cultures.

Example of Sesquiterpenoids

• a natural monocyclic sesquiterpene

alcohol

• a colorless viscous oil

Bisabolol(没药醇)

• a colorless viscous oil

• almost insoluble in water

• well soluble in ethanol

α-(-)-bisabolol

Example of Sesquiterpenoids

has a weak sweet floral aroma and is used in various fragrances.

Be used for hundreds of years in cosmetics because of its perceived skin healing properties.

Bisabolol(没药醇)

skin healing properties.

anti-irritant

anti-inflammatory

anti-microbialα-(-)-bisabolol

DiterpenoidsDiterpenoids

Diterpenoids

Diterpenes are composed for four isoprene units and have the molecular

formula C20H32. They derive from geranylgeranyl pyrophosphate (焦磷酸牻焦磷酸牻焦磷酸牻焦磷酸牻

牛儿基牻牛儿牛儿基牻牛儿牛儿基牻牛儿牛儿基牻牛儿酯酯酯酯).

Examples of diterpenes are cafestol (咖啡醇咖啡醇咖啡醇咖啡醇[抗炎抗炎抗炎抗炎药药药药]), kahweol (咖啡白脂咖啡白脂咖啡白脂咖啡白脂),

cembrene (西柏西柏西柏西柏烯烯烯烯)and taxadiene (precursor of taxol). cembrene (西柏西柏西柏西柏烯烯烯烯)and taxadiene (precursor of taxol).

geranylgeranyl pyrophosphate

cafestol cembrene

Diterpenoids

Diterpenes also form the basis for biologically important compounds such

as retinol (维生素维生素维生素维生素A), retinal (维生素维生素维生素维生素A醛醛醛醛), and phytol (叶叶叶叶绿醇绿醇绿醇绿醇). They are kn

own to be antimicrobial and antiinflammatory. The herb Sideritis(唇形科毒唇形科毒唇形科毒唇形科毒

马草属马草属马草属马草属) contains diterpenes.

retinol retinal

Structure ----Diterpenoids

Acyclic diterpenoids

CH2OHphyt olBicyclic diterpenoids

Monocyclic diterpenoids

CH2OHvi t ami n ATricyclic diterpenoids Tetracyclic diterpenoidsBicyclic diterpenoids

O

OHO

CH2OHHO

andrographolide

Tricyclic diterpenoids

COOHpi mar i c aci d

Tetracyclic diterpenoids

H

H

H

kaurene

Example of Diterpenoids

Phytol

• is a a key acyclic diterpene alcohol that is a

precursor for vitamins E and K1.

• is an extremely common terpenoid, found in • is an extremely common terpenoid, found in

all plants esterified to Chlorophyll (叶叶叶叶绿素绿素绿素绿素)

to confer lipid solubility.

• is found in petroleum sediments.

Example of Diterpenoids

Cembrene

• a natural monocyclic diterpenoid• a colorless oil with a faint wax-like odor.

• Cembrene itself has little importance as• Cembrene itself has little importance aschemical entity, being a trail pheromone for termites (白白白白蚁蚁蚁蚁);

• the chemical structure of cembrene is central to a very wide variety of other natural products found both in plants and in animals.

Example of Diterpenoids

Overview• a mitotic inhibitor (有有有有丝分裂抑制剂丝分裂抑制剂丝分裂抑制剂丝分裂抑制剂) used in

Taxol (Paclitaxel)

• a mitotic inhibitor (有有有有丝分裂抑制剂丝分裂抑制剂丝分裂抑制剂丝分裂抑制剂) used in cancer chemotherapy

• 1967, Wall and Wani • Pacific yew tree, Taxus brevifolia

• Bristol-Myers Squibb (BMS) • taxol ---- paclitaxel ---- trademark 'Taxol‘

Example of Diterpenoids

Overview

Paclitaxel is now used to treat patients with • Lung cancer

Taxol (Paclitaxel)

• Lung cancer• Ovarian (卵卵卵卵巢的巢的巢的巢的) cancer• breast cancer• head and neck cancer,

Example of Diterpenoids

Overview

Paclitaxel works by interfering with normal microtubule (微管) breakdown during cell division. Together with docetaxel (多西紫杉醇多西紫杉醇多西紫杉醇多西紫杉醇),

Taxol (Paclitaxel)

it forms the drug category of the taxanes (紫杉紫杉紫杉紫杉烷类烷类烷类烷类 ).

Example of Diterpenoids

Overview

As well as offering substantial improvement in patient care, paclitaxel has been a relatively controversial drug.

There was originally concern because of the

Taxol (Paclitaxel)

environmental impact of its original sourcing, no longer used, from the Pacific yew.

In addition, the assignment of rights, and even the name itself, to Bristol-Myers Squibb were the subject of public debate and Congressional hearings.

Example of Diterpenoids

Taxol (Paclitaxel) Undisturbed Pacific Yew

bark contains paclitaxel

and related chemicals

The bark is peeled and

processed to provide

paclitaxel

Example of Diterpenoids

Taxol (Paclitaxel)

From 1967 to 1993, almost all paclitaxel produced

was derived from bark from the Pacific yew, the

harvesting of which kills the tree in the process.

While there was considerable uncertainty about While there was considerable uncertainty about

how large the wild population of Taxus brevifola

was and what the eventual demand for taxol would

be, it had been clear for many years that an

alternative, sustainable source of supply would be

needed.

Example of Diterpenoids

Taxol (Paclitaxel)

Initial attempts used needles from the tree, or

material from other related Taxus species, including material from other related Taxus species, including

cultivated ones. But these attempts were bedevilled

by the relatively low and often highly variable yields

obtained. It was not until the early 1990s, at a time

of increased sensitivity to the ecology of the forests

of the Pacific North West, that it was successfully

extracted on a clinically useful scale from these

sources.

Example of Diterpenoids

Taxol (Paclitaxel)

From the late 1970s, chemists in the US and France

had been interested in taxol. A number of US groups

attempted a total synthesis of the molecule, starting

from petrochemical-derived starting materials. This from petrochemical-derived starting materials. This

work was primarily motivated as a way of generating

chemical knowledge, rather than with any expectation

of developing a practical production technique.

By contrast a French group of Pierre Potier quickly

recognized the problem of yield. They populated by

the related yew Taxus baccata, so that needles were

available locally in large quantity.

Example of Diterpenoids

Taxol (Paclitaxel) By 1981 they had shown that it was feasible to

isolate relatively large quantities of the compound

10-deacetylbaccatin, a plausible first step for a

semi-synthetic production route to taxol.

By 1988 they co-published such a semi-synthe-

tic route from needles of Taxus baccata. The view tic route from needles of Taxus baccata. The view

of the NCI, however, was that even this route was

not practical.

10-deacetylbaccatin

Example of Diterpenoids

Taxol (Paclitaxel)

By 1988, and particularly with Potier's publication,

it was clear to Holton as well that a practical semi-

synthetic production route would be important.

By late 1989, Holton's group had developed a semi-

synthetic route to paclitaxel with twice the yield of the

Potier process. Florida State University, where

Holton worked, signed a deal with Bristol-Myers

Squibb to license this and future patents.

Example of Diterpenoids

Taxol (Paclitaxel)In 1992, Holton patented an improved process with

an 80% yield. BMS took the process in-house and

started to manufacture paclitaxel in Ireland from 10-

deacetylbaccatin isolated from the needles of the Euro

pean yew.

In early 1993, BMS were able to announce that they

would cease reliance on Pacific yew bark by the end

of 1995, effectively terminating the ecological contro-

versy over its use. This announcement also made

good their commitment to develop an alternative

supply route, made to the NCI in their CRADA

application of 1989.

Example of Diterpenoids

Taxol (Paclitaxel)Currently, all paclitaxel production for BMS uses

plant cell fermentation (PCF) technology developed

by the biotechnology company Phyton Biotech, Inc

and carried out at their plant in Germany.

This starts from a specific taxus cell line propagated This starts from a specific taxus cell line propagated

in aqueous medium in large fermentation tanks. Pacli-

taxel is then extracted directly, purified by chromato-

graphy and isolated by crystallization. Compared to

the semi-synthesis, PCF eliminates the need for many

hazardous chemicals and saves a considerable amount

of energy.

Example of Diterpenoids

Taxol (Paclitaxel)In 1993 it was discovered that taxol was coinciden

tally produced in a newly described fungus living in

the yew tree. It has since been found in a number of

other endophytic fungi, opening the possibility of

taxol production by culturing one of these fungal

species.species.

The initial motivation for synthetic approaches to

paclitaxel included the opportunity to create closely

related compounds. Indeed this approach led to the

development of docetaxel.

Example of Diterpenoids

Ginkgolides

Ginkgo is a genus of highly unusual

non-flowering plants with one extant

species, G. biloba, which is regarded

Ginkgolides are biologically active terpenic lactones present in Ginkgo

biloba.

They are bicyclic diterpenoids, and there are six lactone-rings in their

skeletons.

species, G. biloba, which is regarded

as a living fossil.

Example of Diterpenoids

Ginkgolide B is an extract from the

cultivated leaves of the Ginkgo Tree.

Clinical studies have shown ginkgo to

benefit short term memory, cardiovas-

cular health, respiratory health and cular health, respiratory health and

gastrointestinal health.

Ginkgolide B is an active platelet

aggregating factor antagonist(对抗物对抗物对抗物对抗物).

All ginkgo formulas must have ade-

quate levels of ginkgolide B in order to

successfully increase c erebral blood

flow.

Example of Diterpenoids

Tanshinones are diterpene quinones

isolated from the roots of Radix Salvia

miltiorrhiza (Danshen), a traditional Chin

ese medicine used in the treatment of car-

diovascular diseases and recently reported

Tanshinones

diovascular diseases and recently reported

to exhibit anti-tumour effects.

The anti-tumour potential of Danshen

was investi-gated by studying the cytoto-

xicity of the major diterpenes, including

tanshinone IIA, cryptotanshinone(隐丹参隐丹参隐丹参隐丹参酮酮酮酮), tanshinone I and dihydrotanshinone

on a human HepG2 cell line in this study.

Tanshinone II A

Triterpenoids

Triterpenoids

Triterpenes consist of six isoprene units and have the molecular formula

C30H48. The linear triterpene squalene (角角角角鲨烯鲨烯鲨烯鲨烯), the major constituent of s

hark liver oil, is derived from t he reductive coupling of two molecules of fa

rnesyl pyrophosphate (焦磷酸法尼焦磷酸法尼焦磷酸法尼焦磷酸法尼酯酯酯酯). Squalene is then processed biosynthet

ically to generate either lanosterol (羊毛甾醇羊毛甾醇羊毛甾醇羊毛甾醇)or cycloartenol (环阿乔醇环阿乔醇环阿乔醇环阿乔醇), the ically to generate either lanosterol ( )or cycloartenol (环阿乔醇环阿乔醇环阿乔醇环阿乔醇), the

structural precursors to all the steroids.

squalene

farnesyl pyrophosphate

lanosterol cycloartenol

• Acyclic triterpenids squalene

• Bicyclic triterpenids

Structure ----Triterpenids

α-carotene

β-carotene

Structure ----Triterpenids

• Tetracyclic triterpenidsDammarane(达玛烷) Lanostane(羊毛甾烷) Tirucallane(甘遂醇)

H H

H

H

H H

H

Hdammarane

H

H

lanostaneH

tirucallane

H

Cycloartane(环木菠萝烷) Cucurbitane(葫芦烷)

cycloartane

H

cucurbitane

H

H

H

H

• Pentacyclic triterpenoids

Oleanane (齐墩果烷齐墩果烷齐墩果烷齐墩果烷) Ursane(乌苏烷乌苏烷乌苏烷乌苏烷) Lupane (羽扇豆羽扇豆羽扇豆羽扇豆烷烷烷烷)

H

H

Structure ----Triterpenids

oleanane

H

H

H

H

ursane

H

H

H

lupaneH

H

H

Example of Triterpenoids

Squalene

Squalene is a natural organic compound originally obtained for

commercial purposes primarily from shark liver oil, though there are

botanic sources as well, including amaranth (苋菜苋菜苋菜苋菜) seed, rice bran (米米米米

), wheat germ ( ), and olives ( 榄榄榄榄). All higher organisms p糠糠糠糠), wheat germ (小麦胚芽小麦胚芽小麦胚芽小麦胚芽), and olives (橄橄橄橄榄榄榄榄). All higher organisms p

roduce squalene, including humans. It is a hydrocarbon and a tri-te

rpene.

Squalane (角角角角鲨烷鲨烷鲨烷鲨烷,异三十异三十异三十异三十烷烷烷烷) is a saturated form of squalene in w

hich the double bonds have been eliminated by hydrogenation. Be

cause it is less susceptible to oxidation, it is more commonly used in pe

rsonal care products than squalene.

Example of Triterpenoids

Squalene

Squalene is a low density compound

often stored in the bodies of cartilaginous

fishes ( 软骨鱼, their skeletons made of c

artilage (软骨)rather than bone) such as s

harks, which lack a swim bladder鳔(动) aharks, which lack a swim bladder鳔(动) a

nd must therefore reduce their body d

ensity with fats and oils. Squalene, w

hich is stored mainly in the shark's liver, i

s lighter than water with a specific g

ravity of 0.855. Environmental and other

concerns over shark hunting have mo-

tivated its extraction from vegetable

sources instead.

Example of Triterpenoids

Squalene

Recently it has become a trend for

sharks to be hunted to process their

livers for the purpose of making livers for the purpose of making

squalene health capsules.

However, there is little clinical

evidence to prove that, taken internally,

squalene does anything to increase an

individual's quality of life.

Example of Triterpenoids

Squalene

Use as a moisturizerUse as a moisturizer

Squalene is used in cosmetics as a natural moisturizer. It p

enetrates the skin quickly, does not leave a greasy feeling on t

he skin and blends well with other oils and vitamins.

Example of Triterpenoids

Squalene

Role in steroid synthesis

Squalene is the biochemical precursor to the whole family of

steroids. Oxidation (via squalene monooxygenase角角角角鲨烯单加氧鲨烯单加氧鲨烯单加氧鲨烯单加氧steroids. Oxidation (via squalene monooxygenase角角角角鲨烯单加氧鲨烯单加氧鲨烯单加氧鲨烯单加氧酶酶酶酶) of one of the terminal double bonds of squalene yields 2, 3-

squalene oxide, which undergoes enzyme-catalyzed cyclization

to afford lanosterol, which is then elaborated into cholesterol (胆胆胆胆

甾醇甾醇甾醇甾醇) and other steroids.

Example of Triterpenoids

Ginsenosides

Ginsenosides are a class of triterpene saponins, found exclusively

in the plant genus Panax (ginseng). Ginsenosides have been the target of

research, as they are viewed as the active compounds behind the claims

of ginseng's efficacy. Because ginsenosides appear to affect multiple of ginseng's efficacy. Because ginsenosides appear to affect multiple

pathways, their effects are complex and difficult to isolate.

Ginsenosides are separated by column chromatography. Ginsenoside

content can vary widely depending on species, location of growth, and

growing time before harvest.

Example of Triterpenoids

Ginsenoside Rb1 • most abundant in Panax quinquefolius

(American Ginseng).

• affect the reproductive system in animal

testicles.

• recent research ---- affects rat embryo(胚胎胚胎胚胎胚胎)• recent research ---- affects rat embryo(胚胎胚胎胚胎胚胎)

development.

• may increase testosterone (睾睾睾睾酮酮酮酮)production

in male rats indirectly through the

stimulation of the luteinizing

hormone (促黄体生成激素促黄体生成激素促黄体生成激素促黄体生成激素).

• inhibits chemoinvasion and angiogenesis.

Example of Triterpenoids

Ginsenoside Rc

• is recognized for producing more sedative

(镇静的镇静的镇静的镇静的) related results than other ginsenosides

• In one particular study on breast cancer and • In one particular study on breast cancer and

different ginsenosides, it was found that only

ginsenoside-Rc was capable of inhibiting the

growth of these cancer cells. This suggests that

there is a possibility that ginsenoside-Rc may

have effects that prevent or limit the develop-

ment of breast cancer.

Example of Triterpenoids

Ginsenoside Rc

• A further study was also able to demonstrate

a possible effect of ginsenoside-Rc on the a possible effect of ginsenoside-Rc on the

motility of sperm (精子活精子活精子活精子活动能力动能力动能力动能力). Data from

this experimentation showed a significant

increase in motility when the sperm was in a

ginsenoside-Rc solution.

Example of Triterpenoids

Ginsenoside Rg1

• most abundant in Panax ginseng (Chinese/

Korean Ginseng). Korean Ginseng).

• Improves the capability of spatial learning

for mice, plus estrogen-like (雌激素雌激素雌激素雌激素) activity

(which could account for the boosting of "yin"

theory)

Essential OilsEssential Oils

Essential Oils

• Terpenes and terpenoids are the primary constituents of the essential oils of many types of plants and flowers.

• Essential oils are used widely as natural flavor additives for food, as fragrances in perfumery, in aroma therapy,and in traditional and alternative medicines. Synthetic and in traditional and alternative medicines. Synthetic variations and derivatives of natural terpenes and ter-penoids also greatly expand the variety of aromas used in perfumery and flavors used in food additives.

ISOLATION & SEPARATION TECHNIQUES

Essential oils containing mono- and sesquiterpenoids are obtaind

by water and or steam distillation of the part such as flowers, lea-

-ves of stems, where the essential oils occur in more concentrated

form. Due to the heat lability of certain constituents of essential oils

different distillation methods have to be used for different raw m-

-erials which are briefly described below:-erials which are briefly described below:

Distillation

Expression

Solvent extraction

Distillation

Today, most common essential oils, such as lavender 熏衣草熏衣草熏衣草熏衣草, peppermint薄荷油薄荷油薄荷油薄荷油, and eucalyptus, are distilled. Raw plant material, consisting of the flowers, leaves, wood, bark, roots, seeds, or peel, is put into an alembic 蒸蒸蒸蒸馏器馏器馏器馏器(distillation apparatus) over water. As the waut into an alembic 蒸蒸蒸蒸馏器馏器馏器馏器(distillation apparatus) over water. As the water is heated the steam passes through the plant material, vaporizing the volatile compounds. The vapors flow through a coil where they condense back to liquid, which is then collected in the receiving vessel.

Distillation

Most oils are distilled in a single process. One exception is Ylang-ylang (Cananga odorata依依依依兰香水树兰香水树兰香水树兰香水树), which takes 22 hours to complete through a fractional distillation.

Distillation

The recondensed water is referred to as a hydrosol水溶胶水溶胶水溶胶水溶胶, herbal distillate馏出物馏出物馏出物馏出物 or plant water essence, which may be sold as another fragrant product. Popular hydrosols are rose water, lavender water, lemon balm香脂 , and orange blossom water. The use of herbal distillates ion balm香脂 , and orange blossom water. The use of herbal distillates in cosmetics is increasing. Some plant hydrosols have unpleasant smells and are therefore not sold.

Expression

Most citrus peel oils are expressed mechanically, or cold-pressed. Due to the large quantities of oil in citrus peel and the relatively low cost to grow and harvest the raw materials, citrus-fruit oils are cheaper than most other essential oils. Lemon or sweet orange oils that are than most other essential oils. Lemon or sweet orange oils that are obtained as by-products of the citrus industry are even cheaper.

Prior to the discovery of distillation, all essential oils were extracted by pressing.

Solvent extraction

Most flowers contain too little volatile oil to undergo expression and their chemical components are too delicate and easily denatured变性的by the high heat used in steam distillation. Instead, a solvent such as hexane or supercritical 超临界的carbon dioxide is used to extract the hexane or supercritical 超临界的carbon dioxide is used to extract the oils. Extracts from hexane and other hydrophobic solvent are called concretes 凝结物 , which is a mixture of essential oil, waxes, resins, and other lipophilic (oil soluble) plant material.

Solvent extraction

Although highly fragrant, concretes contain large quantities of non-fragrant waxes and resins. As such another solvent, often ethyl alcohol, which only dissolves the fragrant low-molecular weight compounds, is used to extract the fragrant oil from the concrete. Tcompounds, is used to extract the fragrant oil from the concrete. The alcohol is removed by a second distillation, leaving behind the absolute.

ISOLATION & SEPARATION TECHNIQUES

• Terpenoids• Following methods are employed for the extraction of mono-, sesqui-,

di-, tri-, and tetraterpenoids.

• Air dried powdered part of the plant is extracted by percolation or soxhlet

extraction successively with organic solvents with increasing polarity such as

petroleum ether, benzene, diethyl ether, chloroform, ethyl acetate, acetone,

ethanol, methanol and water. The extraction efficiency can be increased with

the decrease in the time of the process by stirring the pulverized plant material

using mechanical stirrer with the chosen solvent and filtering it to obtain the

extract.

STRUCTURE ELUCIDATION

• Physical Mehtods1. Molecular formula

2. Specific rotation

3. Refractive index

• Spectral Methods for Structure Determination• Spectral Methods for Structure Determination1. UV

2. IR

3. MS

4. NMR

Physical Mehtods

1. Molecular formulaDetermination of the molecular formula of an isolated pure terpenoid is done by finding

out the empirical formula and molecular weight. Empirical formula can be found out by elemental

analsis .While molecular weight can be determined by vapour density, elevation of boiling

point and depression of freezing point.

2. Specific rotationSpecific rotation of a compound is measured to ascertain the optical activity exhibited by it. It helps

to distinguish between optical isomers.

3. Refractive indexIt is measured to calculate the value of molecular refraction, which is useful to find out the nature

of the carbon skeleton especially in the case of sesquiterpenoids .

Spectral Methods

1. UVFunctional groups, present in terpenoids , which absorb in the UV range between 200-350nm are termed as chromophores.However UV data becomes valuable only when the terpenoid molecule contains conjugated double bondsand/or α,β-unsaturated carbonyl group.

2. IR2. IRThis method is routinely used for the identification as well as the structure elucidation of new terpenoids.

3. MSFAB-MS affords the e xact molecular ion peak along with diagnostic fragmentation patterns of the terpenoid molecule. It is an important tool forthe structure determination .

Spectral Methods

4. NMR

• NMR spectroscopy comprising of both PMR and CMR is in fact one of the

Most important tools furnishing a good teal of information required for the

structure elucidation.

The combination of 1D selective and 2D NMR techniques such as COSY,

TOCSY, ROESY,2D IN-ADEQUATE, HMQC, HMBC COLOC, HOHAHA,

HETCOR and selective INEPT are of great value for the structure elucidation

of various terpenoids including the saponins and glyosides of a number

of sugar moieties.

EXAMPLE

• C10H16O• b.p.77℃℃℃℃• UV:236nm• IR:1665，，，，1625，，，，1603，，，，1398，，，，1190，，，，

1117cm-1.• MS:m/z 69(100),41,84,94,109,67,83,81• 1H-NMR:1.65(6H，，，，d，，，， C-7 methyls) ，，，，

2.15(3H，，，，s，，，，C-3 Me)，，，，5.0(1H，，，，t，，，，

CHO

2.15(3H，，，，s，，，，C-3 Me)，，，，5.0(1H，，，，t，，，，H-6)，，，， 5.8(1H，，，，d，，，，H-2)，，，， 9.84(1H，，，，

d，，，，H-1).• 13C-NMR:190(C-1)，，，，127.5(C-2)，，，，16

2.1(C-3)，，，，40.5(C-4)，，，，26.5(C-5)，，，，123.5(C-6)，，，，132.3(C-7)，，，，25.3(C-8)，，，，17.4(C-9)，，，，17.0(C-10).

geranial

DiterpenoidsTypes of Terpenoids

Outcome

• Student understood the terpenoids in the form

of

�Meaning,

�Different types�Different types

�Properties, occurrences, uses

� Isolation Method

�General Biogenetic Pathway

�Pharmacognostic account of different drug con

taining important constituents Terpenoids.