Med Chem 1 Flashcards
Pharmacognosy is…
…the study of the physical, chemical, biochemical, and
biological properties of drugs, drug substances, or
potential drugs or drug substances of natural origin, as
well as the search for new drugs from natural sources
Natural Drugs…
Natural product screening
What pools can we take from?
• Plant kingdom (e.g. Morphine, cocaine, salicin, quinine, taxol)
• Microbial world (e.g. Penicillin and statins)
• Marine world (e.g. curacin A, obtained from a marine cyanobacterium)
• Animals (e.g. Epibatidine from the skin of the Ecuadorian poison frog)
• Toxins (venoms) (e.g. Teprotide, a peptide isolated from the venom of the Brazilian pit viper)
The plant kingdom
-is a plentiful, rich supply of complex &
varied chemical compounds
Plant species in Rainforest:
- untapped source
- still waiting to be discovered
Plant Extracts
Plants did not evolve for the purpose of producing medicines
~ 320,000 plant species on the planet
25,000 used in folk medicine
Only 120 active principles used around the world
UK has < 40 in regular use
• Chemicals in plants
- many have a role as irritants or toxic materials that provide
defense against predators (herbivores, omnivores)
Herbal Remedies
• Experimentation with berries, leaves & roots
• Local healer brews
• Often useless & dangerous
• Example of Placebo effect - state of mind, no real differences
• 80% of worlds population use herbal drugs as part of their normal health care routine
• In the USA it is the fastest growing segment of pharmacy trade
• They tend to be far less expensive than prescription drugs
• They are not pure substances (they contain many consitituents)
• They are not standardised or analysed for the
content of the active principle
• Definition of a herb:
- a crude material containing multiple
pharmacologically active compounds - Is a substance of plant origin
- May contain dozens of different compounds
- Can have its composition (and quality) verified using HPLC
- May contain some compounds that reinforce others
Herbal medicines may work through..
synergy
In other words, the mixture acts together (many complex
structures and interactions) to generate a beneficial effect
Example of interaction
A patient taking coumadin (warfarin) who also starts taking ginkgo (= gingko) biloba extracts (which affects platelet-activating factor, PAF) can effectively cause an overdose effect of
coumadin leading to bleeding as a result of
excessive blood thinning.
Ginkgo biloba extracts
Ginkgo biloba extracts include ginkgolide A and B
Ginkgo biloba extracts produce vasodilatory effects on both the arterial and venous circulation (increasing both peripheral &
cerebral blood flow)
Chinese herbal medicine
produced antimalarial agent (artemisinin)
A good illustration of how natural products tend to be:
- complex structures and therefore novel
- hard to synthesise in the lab
Natural Drugs…
Reserpine - From the Indian snakeroot plant
- Indole nucleus
- Light yellow crystalline alkaloid
- Breaks down in presence on light (especially in clear glass containers)
- Able to reduce blood pressure
Natural Drugs…
SALICIN
• A glycoside
• Isolated in 1829
• Synthesised in 1979
- 1870 Marcellus von Nencki showed salicin is converted in the body to salicylic acid (antipyretic)
Natural Drugs…
QUININE
The Quechua Indians of Peru used the bark of the Cinchona tree as a muscle relaxant, thus stopping the shivering brought on by cold weather.
The active ingredient in this remedy is quinine which is now used to treat malaria.
• Arrests patient fevers
• Variable responses of patients to treatment with cinchona bark
• Led to isolation of active principle (1811, Bernardino Gomez,
Portuguese surgeon, isolated silvery crystals)
Natural Drugs… names
- Morphine from the opium poppy - Ancient Egypt
- Reserpine from the snake-root plant - India
- Salicin from the willow tree - Medieval England
- Quinine from cinchona bark - Aztecs (S. America)
More recent examples of natural drugs…
Combretastatin
• Isolated (in 1982) from the South African tree Combretum caffrum
• A potent cytotoxic against a wide variety of human cancer cells
• Poor water solubility is the main drawback
• Still in clinical trials but may be the next anticancer drug of choice
TAXOL® (Paclitaxel)
• Screening program in 1960 by US National cancer institute
• Used plants gathered by US Department of Agriculture (bark,
twigs, leaves & fruit of the Pacific Yew tree)
• in vitro studies showed Taxol® had cytotoxic activity
• Chemical structure reported in 1971
• Synthesised in 1994 by 2 groups
• R.A. Holton (Florida State University)
• K.C. Nicolaou (Scripps Research Institute)
Used in:
Ovarian cancer
Metastatic breast cancer
Lung cancer
Prostate cancer
Alkaloids…
Alkaloids - are amines found in plants,
e.g. in seeds, roots, bark & leaves
IS MORPHINE AN ALKALOID?
YES! IT HAS A TERTIARY AMINE
AND IS FOUND IN THE OPIUM JUICE FROM A SPECIES OF POPPY
Semi-Synthetic Drugs…
Aspirin® - marketed by Bayer after curing toothache (highlighting its analgesic properties)
Semi-Synthetic Drugs…
Taxol: Example 1
4 Pacific Yew Trees / patient !!!
Therefore we make use of a semi-synthetic approach:
- harvest a bio-synthetic intermediate
e. g. 10-deacetylbaccatin III (easier to extract from the tree since it is found in the needles belonging to the tree)
Semi-Synthetic Drugs…
Taxol: Example 2
Taxotere (docetaxel)
Is a semi-synthetic taxoid.
Approved for the treatment of advanced breast cancer (in 1996)
Semi-Synthetic Drugs…
Galanthamine - from European daffodils & snowdrops
• A tertiary alkaloid
• Beneficial to patients with mild Alzheimers Disease (AD)
- significant improvements in performance & attention
• Galanthamine is extremely expensive ($50,000/kg)
• First successful synthesis of (-)-galanthamine was in 1962 by Barton
• Also prepared by a stereospecific reduction of (-)-narwedine
Heroin
Semi synthetic drug
Synthetic Drugs…
e.g. drugs originating from the screening of dyes (the dye industry)
Paul Ehrlich - made an important contribution
Initial work involved the use of natural dyes & analogues in histological staining (staining microbes & viewing them under microscope)
- his thesis was critical of histologists failing to base their work on a theoretical understanding of how dyes bind to tissue components
- He suggested size and chemical structure were important for uptake and distribution in cellular and animal models (e.g.
lipophilicity).
Synthetic Drugs…
Methylene blue - Ehrlich & Guttman
5 capsules of 100mg / day, cured patients from malaria
This was the first instance of a synthetic drug being used
with success against a specific disease
Synthetic Drugs… Antibacterial azodyes
Chrysoidine (1913)
Possessed powerful antiseptic properties
Phenazopyridine (1933)
Urinary antiseptic (relief for urinary tract pain)
Synthetic Drugs… Heterocyclic Sulfonamides
A potent antibacterial sulfonamide
Winston Churchill (1943) - British PM saved by research initiated in Germany Reduced mortality in pneumonia patients from 1 in 4, to 1 in 25
Natural products Vs Synthetic compounds
Generally speaking, natural products have:
• More protonated amine & free hydroxy functionalities
• More single bonds
• More fused rings containing more chiral centres
Natural products & synthetic compounds occupy different
regions of chemical space.
Each contribute to the overall chemical diversity needed in
drug discovery
