Natural Products

Fredryk Mandey, M.Sc.,PhD.,MRSC., MSoCI

Recommended text: "Chemical Aspects of Biosynthesis" by J. Mann 574.192

Man - in the heavy demand section of the QML,
also available in Blackwells (£ 11,99)
 Natural products and the drug market

 medicinal plants play a dominant role in the primary healthcare

of 80% of the world’s population – there are written records going
back 5000 years detailing the use of plants as medicines
in the remaining 20% of the world’s population 50% of drugs in
clinical use are of natural origin
the current global value of drugs derived from plants has been
estimated at £23 billion annually
natural products continue to play a leading role in the discovery
of drugs in pharmaceutical firms
 Natural products and the drug market

Drug Indication
Atorvastatin High cholesterol
Enalapril High blood pressure
Simvastatin High cholesterol
Captopril High blood pressure
Fluticasone propionate Asthma
Amoc-Clav Acid Antibiotic
Ciclosporin A Organ transplants

Of the world’s 25 best-selling pharmaceuticals 12 are either of natural origin

or were designed based on a natural product lead structure
Opium poppy
Papaver somniferum
origin: Asia minor
 Origin of opium

• opium alkaloids such as morphine, codeine are obtained from cultures of

opium poppy
• in part, they are transferred in to partial synthetic derivatives
• legal cultivation is subject to international treaties
• legally grown in Bulgaria, Greece, India, Iran, Turkey
 How to obtain opium

opium represents the dried latex of opium poppy (Papaver

somniferum), and is harvested by scratching its capsules
 Cultural history of opium poppy

“sleeping goddess of Gazi”, earrings found in the tomb of king

approx 1300 - 1250 B.C., today at Siphatah and queen Tausrit (Egypt),
museum in Heraklion (Crete) dating from approx 1550 B.C.
 Natural products found in opium

HO H3CO

O H O H
CH3 CH3
N N

HO HO

morphine codeine

highly potent analgesic drug potent cough suppressant

strong analgesic drug

Class A drug Class B drug

prescription-only Controlled Drug medicines

 Drugs derived from opium alkaloids

HO

AcO O
N

O H H3CO
CH3
N HO CH3

AcO H3C CH3

CH3

heroin buprenorphine
illegal intoxicant
highly potent analgesic drug
5 – 10 x more potent than morphine,
extremely high risk of addiction
Cannabis and cannabinoids
Cannabis sativa ssp. indica (Indian hemp)
since ancient times cultivated for its fibres
Illicit use of cannabis

hashish, charas: dried resin which

is obtained from female
inflorescences (7 – 14%)
sinsemilla, ganja: dried tips of
female plants (4 – 5%)
marijuana, bhang (grass): dried
leaves and flowers
(2 – 5%)

figures in parentheses:
average content in D9-THC
 Important natural products from cannabis

CH3

OH
H H

H3C
O CH3
H3C

D9-tetrahydrocannabinol

• D9-THC is euphorigenic and provokes hallucinations

• does not lead to physical dependence, but to psychological
dependence (or addiction)
• ongoing clinical trial to evaluate as analgesic drug to be used
to treat pain associated with multiple sclerosis, shingles, stroke,
or cancer
 Cocaine and coca leaves

"...contains the valuable NERVE STIMULANT and TONIC properties of the coca plant..."
"...a delicious, exhilarating, refreshing and invigorating beverage..."
 Erythroxylum coca
domesticated since ancient times, wild forms no longer known
nowadays cultivated in Peru, Colombia, Bolivia, and Brazil
 Pharmacological properties of cocaine

COOCH3

H3C N
O

cocaine

• potent local anaesthetic (originally used mainly in dentistry, nowadays

completely replaced by synthetic local anaesthetics )
• causes vasoconstriction (leading to congenital malformations when
consumed during pregnancy)
• potent central nervous system stimulant with a pronounced risk of
addiction
 LSD (Lysergic acid diethylamide)

O
CH3
H3C N N
H
H3C

NH

• synthesized in 1938 by Albert Hoffmann, based on compounds from ergot

• a semisynthetic psychedelic drug with a pronounced hallucinogenic potential
• extremely popular in the 1960s (pop and rock music)
• street names include “acid“, “trip“, “hits“, “sugar cube“, “cid“, “doses“
 “Magic mushrooms”

in use: Psilocybe sp. div. (e. g. liberty cap)

Panaeolus sp. div.
Conocybe sp. div.
further genera such as Stropharia, Inocybe, Copelandia etc.
most of them represent LBMs with no characteristic features!

NH(CH3)2 N(CH3)2
OPO3H OH

N N
H H
psilocybin psilocin
symptoms: dizziness, vertigo, impaired balance, state of intoxication,
restlessness, agitation, hallucinations
© Dr. Joachim Czichos
 Life threatening “magic mushrooms“

„recommended “ species: Amanita muscaria (fly agaric)

Amanita pantherina (panther cap)

H3N H3N
COO NH3 COO

O O HN O
HO O
N N

ibotenic acid muscimol muscazon

symptoms: sleepiness, restlessness, intoxication, agitation,

hallucinations
Amanita muscaria (fly agaric) Amanita pantherina (panther cap)
 Plant-derived hallucinogens

plants Atropa belladonna (deadly nightshade) CH3

commonly Datura stramonium (jimson weed) N

used: Hyoscyamus niger (black henbane) O

CH2OH

Mandragora officinarum (mandrake) O

scopolamine

• all of them belong to the nightshade family (Solanaceae)

• lead to daze, mild euphoria, delirium, state of confusion, but only
rarely to hallucinations
• danger of addiction is rather low, since usually followed by amnesia
• pronounced side effects (e. g. tachycardia, dilated pupils, giddiness, nausea,
blurred vision)
Willow bark gave the idea for a painkiller

COOH

O CH3

acetylsalicylic acid
(aspirin®)

CH2OH OH

HO OH
O O CH2OH

lead structure

salicin
Taxol – an anticancer agent from yew tree

O O
HN O
O
OH
HO O

H
HO
O O
O O

O
Penicillins – the start of industrial exploitation of microorganisms

• in 1928, Sir Alexander Fleming discovered an antibiotic produced by a

strain of Penicillium notatum
• Florey and Chain and developed method of mass producing the drug by
fermentation
 Penicillins and cephalosporins – the basis for modern antibiotics

H H H
H N
HOOC N S
S

NH2 N O N
O
O O

Penicillin N - natural Penicillin G - semisynthetic

H H
HOOC N S

NH2 O N O CH3
O
COOH O

Cephalosporin C - natural

• these antibiotics revolutionised the treatments of bacterial infections

• the penicillins are still used for respiratory infections, but resistant strains
are a real problem
 Fermentation of microorganisms for drug production

static culture in Erlenmeyer flasks

industrial scale fermenters

 The sea as a habitat

• more than 70% of the earth‘s surface is covered with water

• tropical coral reefs are among the most diverse habitats on our planet

• it is only since 1972 that marine organisms are systematically

investigated for pharmaceutically relevant compounds
Tropical coral reefs

Above sea level ...

Tropical coral reefs

... and below

Tropical coral reefs

... and below

Biodiversity in a coral reef
A life in paradise - or maybe not?!

• tropical coral reefs are among the most densely

populated habitats on earth

• there is a high degree of competition for the

limited resources such as space

• there is a very high evolutionary pressure by

predators, especially fishes

• most members of the reef community are sessile,

i. e. they cannot swim away

• in the course of evolution, most inhabitants of coral

reefs have developed natural products for their
own chemical defense
Possible functions of marine and terrestrial natural products

Examples for biological activity:

– antibacterial
– fungicidal
– insecticidal
– molluscicidal
– cytotoxic
– deterrent against mammals or fishes

 protection against predators

 protection against microbial films ("biofouling")
 deterrency against competitors for space (“allelopathy”)
Cone snails: hunters using poisoned arrows
Cone snails: hunters using poisoned arrows
 Ziconotide, the first drug from the sea
• isolated from the cone snail, Conus magus

• w-conotoxin MVIIA (SNX-111)

• recently approved as a new analgesic

H2N Cys1 Lys2 Gly3 Lys4 (pain killer)

H2N Cys
25
Ala
6 5
Gly
• mechanism of action is different to that of
morphine
Cys16 Cys15 Asp14 Tyr13 morphine

Lys24 Thr17 Lys7 Met12

Gly23 Gly18 Cys8 Ser9 Arg10 Leu11

pain ziconotide
22 19
Ser Ser

Arg21 Cys20

pain
 Ecteinascidin 743, a new anti-tumor drug still being developed

OCH3
CH3 HO CH3

O O H H
H
H3 C CH3
N
N
O H
O H OH
O S
O
H3CO
NH
• isolated from the seasquirt, Ecteinascidia turbinata
HO
• alkylates DNA (in the minor groove)
• phase II clinical trials were already successfully
passed in Europe and USA (developed by
PharmaMar, Spain)
• model project for natural products delivered by
mariculture (yield at the moment 200 g per year)
 Natural products in drug discovery
COLLECT ORGANISM

EXTRACT

SEPARATE COMPONENTS
ACTIVE
TEST FOR BIOLOGICAL ACTIVITY
ACTIVE
NOT ACTIVE PURE COMPOUND

FIND STRUCTURE

GET MORE
NO
MODIFY

APPROVAL
YES

£££££££££
 From cocaine to the dentist

• Sigmund Freud, father of psychoanalysis, used cocaine and observed that

it numbed his tongue
• Eye surgeons were looking for a local anaesthetic and observed that
cocaine might be suitable
• It was used, but there were toxicity problems and it caused irritation
 1884
OMe
Me
N

O
O

O
cocaine
1885
Me Me
N N

OH

O O
Tried atropine
Weak L.A. O
O
Really toxic

homatropine benzoyltropine
Weak, but better Best – not as good as cocaine
still irritant
1896

Are both rings

N
R = COAc necessary?
O R=H First burns skin
Second potent L.A.
R
O
Still irritant
eucaine
1896 NH2 OH
1902 NH2

OH NH2
Topical L.A.
Not water soluble
Can’t inject

MeO O MeO O O O

benzocaine
1903

First safe non-irritant

injectable L.A.
Me2N
O O

amylocaine
early 1900's NH2
Combine amylocaine &
benzocaine least irritant
Action too brief – need
to localise
Et2N
O O

novocaine/procaine
HO
1948 NHMe

NH NEt2
Still used in dentistry
nowadays – localised
O OH
by use of adrenalin
Gives long and intense
OH
xylocaine anaesthesia
adrenalin
 How a compound becomes a drug
time frame (years)

lead discovery (isolation, synthesis) 1-2

pharmacological tests / screening 3-5

toxicity, analytics 6-9

clinical trials 10 - 15

approval introduction on the market

 for 100.000 tested compounds, one will eventually become a drug!

 cost for development approx 300 million £

 after launch, patent coverage will last on average for another 8 years
 Stages of clinical trials

preclinical trials on animal populations

 dose finding, metabolism, toxicity

phase I small group (20-80) of healthy volunteers

 safety, tolerability, metabolism

phase II on larger groups (20-300)

 clinical efficacy, dosing requirements

phase III large patient groups (300–3000)

 efficacy in comparison with current
standard treatment

approval

phase IV post-launch safety surveillance

 The complete history of medicine

“That root is heathen.

1985 AD
“Here, eat this root” Here, say this prayer instead”
1940 AD
1850 AD
N
O
W
2000 BC 1000 AD
“That prayer is nothing but superstition.
Here, swallow this potion instead”
“That potion is nothing but snake oil.
Here, swallow this pill instead”
“That pill is totally ineffective.
Here, take this antibiotic instead”
“That antibiotic is no longer effective.
Here, eat this root”