PY5010 Pharmacognosy

★ Definition
○ The study of the physical, chemical, biochemical and biological properties of
drugs, drug substances or potential drugs/substances of natural origin as well
as the search for new drugs from natural sources
○ Includes analysis of whole extracts for efficacy
★ Natural sources
○ Vital source of new drugs but come at a cost:
■ Expensive – ~$1bn to bring a new drug to market
■ Limited success
■ Success rate ~1%
○ Compounds have a higher degree of complexity
■ Plants use enzymes to bring about complex chemical changes that
are not always possible in the lab
○ Vast amount of biodiversity remains to be explored in the plant kingdom
○ Marine products largely untapped – accessibility issues
○ Compounds from microbial sources gaining more attention
○ Success quite low but some significant discoveries drive enthusiasm
★ How to find natural sources of drugs?
○ High throughput screening
■ Free of charge to people in the field
○ Ethnomedicinal approach
■ Look at what traditional healers are using to treat disease – look at
those plants
● Validates the use of the plant as well as finds new drugs
○ Ecological approach
■ Look at various aspects of animal behaviour and eating patterns as
well as plant defence mechanisms
○ Metabolomics
■ Global metabolite profile of an extract
● Doesn’t help with extract choice but can speed up analysis
○ Computational methods
■ In silico screening, ligand docking, reverse pharmacognosy
★ Ethical issues
○ Who owns the intellectual property?
■ Traditional healer?
■ Community?
■ Country as a whole?
■ Academic who identified the lead?
■ Industrial partner?
○ Hoodia
★ Challenges
○ Stability of isolated compound from plant matric
○ Synergy
○ Supply and impact on environment
○ Synthesis vs. isolation from natural sources
○ If using crude extract issues around reproducibility, quality control, wild vs.
cultivated plant source
○ Local legislation
★ Antimalarials
○ Two most used antimalarials are natural products – quinine and artemisinin
○ Malaria caused by protozoan parasite carried by mosquitoes
■ Four species – plasmodium vivax, falciparum, ovale and malariae
■ Falciparum most deadly
○ Quinine
■ Alkaloid and basic amine
■ Isolated from bark of cinchona tree
■ Medicinal properties first discovered by Quechua people of Peru and
Bolivia and brought to Europe by Jesuits
■ Antipyretic, antimalarial, anti-inflammatory, analgesic properties
■ Can cause ear ringing and partial deafness
■ Currently a Tx rather than prophylactic
■ Chloroquine more commonly used
■ From 1961 onwards the parasite has developed resistance to these
drugs especially in sub-Saharan Africa
● Parasite appears to have a cell membrane protein which can
pump the drug out of the cell
○ Artemisinin
■ Chinese herbalists have made a tea for over 2000 years from
Artemisia annua (sweet wormwood)
■ Used for chills, fever and malaria
■ Active ingredient isolated and identified as artemisinin
■ Effective against Plasmosium falciparum and chloroquine resistant
strains of malaria
■ 7 asymmetric centres
■ Stable to light and heat
■ Analogues synthesised to study structure-activity relationships
● Prepared from artemisinin
● Synthesis not practical
■ Dihydroartemisinin, artemether arteether and sodium artesunate are
more active than artemisinin so lactone carbonyl not crucial
■ Deoxyartemisinin poorly active so endoperoxide link is important
■ MoA
● Ferrous ions reduce endoperoxide ring to form radicals
○ Radicals oxidise vital biomolecules in the parasite
resulting in cell death
● Parasite infects red blood cells of the host, releasing iron from
heme
○ This reacts with artemisinin resulting in its own death
★ Anticancer compounds from natural sources
○ Camptothecin
■ Cytotoxic alkaloid from chinese bush Camptotheca acuminata
■ Topoisomerase 1 inhibitor
● Topoisomerase relaxes supercoiled DNA and alleviates helical
constraints – important in DNA synthesis
■ Selective for cancer cells with a higher topo 1 level
■ Lactone essential for activity but is not water soluble and toxic
■ Semi-synthetic analogues irinotecan and topotecan have alcohol or
amine groups to aid solubility
● Also less toxic
★ Tubulin polymerisation inhibitors
○ Vincristine, vinblastine, vindesine and vinorelbine
■ From Madagascan periwinkle, Catharanthus roseus
○ Spongistatin 1
■ From marine sponge in the Maldives
○ Podophyllotoxins
■ Group known as lignans from American mandrake, May Apple
(Podophyllum peltatum) and Humalayan (Podophyllum emodi)
■ Used >1000 years to treat cancer as well as other things
○ Cryptophycins
■ Isolated from blue-green algae
■ Cryptophycin 52 being considered for clinical trials
○ Combretastatins
■ African Bush Willow (Combretum caffrum)
■ Used by Zulu people to ward off evil spirits
○ Inhibition
■ Paclitaxol
● Isolated from Pacific Yew (Taxus brevifolia)
● Initially isolated from bark – not renewable source
● Produced semi-synthetically from an analogue found in the
leaves
○ Now produced via cell culture
■ Other examples
● Pancratistatin
○ Isolated from pancratium littoralis (Narcissus genus –
daffodils)
○ Used in 200BC by Hippocrates to treat breast cancer
● Bryostatin 1
○ Marine invertebrate off the coast of California
○ Boosts immune system to fight cancers and can be
used in combination with other drugs
● Dolostatins
○ Marine sea hare off Mauritius
● Cephalostatin
○ From marine worm
★ Plant glycosides
○ Consist of an aglycone and sugar unit (which may consist of one or more
sugar units)
○ Cardiac glycosides used as either arrow poisons or heart simulants
■ Difference in doses between therapeutic and toxic levels is very small
○ Two main groups known
■ Cardenolides e.g. digitoxigenin from Digitalis purpurea
■ Bufadienolides e.g. hellebrigenin from Helleborus niger