sources of drugs

PHA3042
2015
Eva.Patak@monash.edu
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Monash University

sources of drugs
source (noun)
a place, person or thing from which
something originates or can be obtained
Oxford dictionary

sources of drugs
natural
synthesised in lab

how are drugs discovered - past

medicine goes hand in hand with disease
diseases introduced with civilised society
originally thought to have either magical or
religious origins
medicines obtained from natural products (NPs)
plants, animals, minerals
Ebers papyrus (c. 1550 BC)
serendipity / empirical knowledge

how are drugs discovered - now

serendipity - accidental discoveries
laboratory (penicillin)
clinic (sildenafil)
rational design (e.g. beta blockers)
chemical modification (e.g. chlorothiazide)
random screening
natural products
previously discovered chemicals
chemical libraries

sources of drugs
despite central role that drugs play in
healthcare most people dont know where
drugs come from
synthetically produced (1st world)
natural products (3rd world)

drugs from natural sources

drugs from natural sources account for over
50% of all drugs in clinical use
of these from plants used in traditional
medicine
of NCEs launched onto market (1981 2002)
52% were NPs, NP-derived or based on NPrelated pharmacophores
87% of categorised human diseases treated
by NPs and related drugs

drugs from natural sources

source material
plants, microorganisms,
vertebrates/invertebrates
predominantly terrestrial

why natural sources

plants, microorganisms, insects & higher
animals possess an extraordinary capacity to
manipulate relatively simple building blocks
(e.g. amino acids) into an enormous structural
array of small drug-like molecules (secondary
metabolites)
e.g. tyrosine morphine (by poppy plant)
cheaper & more efficient than organic chemist!

secondary metabolites
possess no obvious primary metabolic function
originally believed to be waste products
now thought to contribute to the producers
fitness i.e. enhance chances of survival
defence against predators or pathogens
can be used both defensively (e.g. plants) or
offensively (e.g. snakes, spiders)
vast array of metabolites (e.g. in plants
>120,000 known structures) which exhibit a
diverse range of pharmacological activity

bioactive molecules
alkaloids
basic nitrogen-containing compound
white crystalline substance
bitter
e.g. morphine, atropine, quinine

glycosides
contains sugar moiety (glycone) + non-sugar
moiety (aglycone)
classified according to chemical nature of
aglycone group
e.g. cardiac glycosides, flavanol glycosides

plants as sources of drugs

use of plants or plant extracts for therapeutic
purposes as ancient as human civilisation
estimated 250,000 - 500,000 plant species on
earth
< 10% systematically studied for bioactive
compounds
20,000 considered to be medicinal plants
drugs are derived from roots, leaves, bark,
seeds & flowers

plants as sources of drugs

development of drugs from plants expensive
1 in 10,000 tested considered promising
of these 1 in 4 approved as new drug
e.g. National Cancer Institute, USA tested plant
extracts for anti-HIV & anti-tumour activity
3 out of 50,000 active against HIV
3 out of 33,000 anti-tumour activity
not screened for other pharmacological
activity

plants as sources of drugs

starting plant material required for discovery,
development & launch of a new drug
bioassays, toxicology & in vivo evaluations
500 mg pure compound from 50 kg raw
material
full pre-clinical & clinical studies
up to 2 kg of pure compound from 200 ton
raw material
need to balance need for new drugs while
preserving natural diversity & the environment

Where to look?

selecting a suitable plant

ethnopharmacology/ethnobotany
observation of use of plants in folk medicine in
different cultures
provide information about pharmacological activity,
doses and intake of drug
specialist - healer
1. culture should be located in floristically diverse
location e.g. rainforest
2. culture remained in region for many generations
3. tradition of healers passing down plant knowledge
from generation to generation
consensus whole village

Healer living in Belize, Central America, collecting the leaves and flowers of the
plant Cornutia pyramidata to include in a mixture used for skin rashes.

selecting a suitable plant

random sampling
taking any plant in sufficient quantity
chemotaxonomic sampling
specific compounds are often only found in
groups of related plants
toxicity / exert an effect on animals
most likely to have active compounds

isolation of active compounds

once plant selected
botanical identification
stabilisation process drying or preserved in
alcohol
extraction solvents
obtain pure compounds
chromatography
undertake bioassay & toxicity testing
bioassay cell culture, isolated organs, in vivo
determine structure

plant-based drug - paclitaxel

US National Cancer Institute established
screening program
in 1962 sample of bark from Pacific Yew found
to have some activity against various tumour
cell lines
active substance isolated in 1969
in 1975 tested on a new assay - melanoma cell
line highly active

plant-based drug - paclitaxel

potent anti-cancer drug
used to treat several types of cancer

however there was a supply problem...

Pacific Yew has restricted habitat (British Colombia)
grows slowly
2.5 kg drug = 27,000 tons bark = 12,000 trees cut
down

needles from other yew species found to

contain baccatin
used to produce semi-synthetic paxlitaxel

animal-based drugs
animals important source of drugs
examples include:
hormones
insulin derived from pancreas of pigs & cows
oestrogen from urine of pregnant mares

heparin
anticoagulant derived from bovine lungs & pig
intestine

animal-based drugs
venoms and toxins of particular interest
found in many vertebrate/invertebrate species
poison dart frogs used for centuries by some
indigenous South American cultures for hunting
venoms highly complex mixtures
contain proteins, polypeptides, enzymes, free
acids

snake venoms
venom often classified as either neurotoxic or
hemotoxic
neurotoxic
produce paralysis (mostly) mediated at neuromuscular
junction
prey / victim dies of respiratory failure

hemotoxic
toxins affect coagulation
increase bleeding

myotoxic (muscles), cardiotoxic, nephrotoxic

discovery of captopril
John Vane a consultant at Squibb interested in
hypertension and believed that angiotensin converting
enzyme (ACE) important in regulating blood pressure
Brazillian post-doc Sergio Ferreria joined Vanes lab and
brought with him extract of Brazilian viper venom
bradykinin potentiating factor
also found to be potent ACE inhibitor

discovery of captopril
initial clinical trials showed decrease in BP when
administered intravenously
peptide not absorbed when taken orally
Squibb then tackled issue of making an oral drug
$1 million/kg to synthesise
captopril went on to become Squibbs first billion dollar
drug
released in Australia in 1982
synthetically synthesised

microorganism-based drugs
prokaryotes make up more than 50% of the
earths biomass
estimated number is 5 x 1030
Important source of many drugs
fungi antibiotics (penicillin), some statins,
ergot derivatives
bacteria antibiotics particularly of genus
Streptomyces e.g. tetracycline, chloramphenicol
still a potential for future drug development

microorganism-based drugs

mine the microbiome for new medicines

use the microbes themselves as drugs

marine - the next frontier

oceans cover 70% of earths surface
potential as a drug source relatively unexploited
access to diversity not present in terrestrial
environments
estimated number of species 0.5-10 million
research into use of marine natural products
still in its infancy
lack of ethnopharmacology
access & collection of organisms

marine - the next frontier

Interest began in 1970s
>10,000 compounds isolated from marine
organisms
sponges, soft corals, sea slugs, seaweeds

defense mechanisms
many sessile invertebrates:
feed by filtering seawater
seawater contains high levels of bacteria
produce anti-bacterial compounds?

cant escape predators

produce toxic compounds?

face competition for space

produce compounds that kill rapidly dividing cells of
neighbouring organisms?

compounds more potent due to dilution in water

drugs from marine sources

examples of drugs that have reached clinical trials
anticancer drugs
bryostatin from bryozoan
discodermolide from sponge
PM-10450 (zalypsis) sea slug
analgesic drug
tetrodoxin (tectin)

summary
untapped pharmacological potential
discovery
access to areas of high biodiversity
United Nations Convention on Biological
Diversity
loss of diversity
cost
natural source vs chemical synthesis

learning outcomes
describe how natural compounds have led to
the development of therapeutics
discuss the potential natural sources still hold
for the development of new therapeutic
entities
understand the issues involved in using natural
sources to develop new therapeutics