Lec 3- Murder, magic and mecidice

Question 1

Why natural products

Answer 1

• Herbals date back to the 16th century but a history of use of natural products goes back to some of the 1st surviving records
• First synthetic production medicine was acetylsalicylate (aspirin) (Bayer 1899)- 25M kg per annum
• Can make far more complex molecules than synthetic chemists- we can then modify them
  
  • Synthetics = less sugar, no chiral centres, sulphones
• Sea snail = ziconotide v.potent analgesic
• Sea cucumber = Trabectedin v.potent anti-cancer drugs

Question 2

Curare

Answer 2

• Toxic animal and plant products have been used since some of the earliest records for hunting, war and executions
• Some of the earliest reports of the use of natural products are as arrow poisons from 1200 BC
• 16th.c explorers came across the use of curare from Chrondrodendron tomentosum mixed with Strychnos
• Early 1800’s Charles Waterton and Claude Bernard experimented with curare and discovered it blocked nerve transmission (respiratory failure)
• Richard Gill eventually managed to persuade 2 drug companies to take it on and tubocurarine was isolated- extensively used as a muscle relaxant in surgery
• Panocurium and atracurium synthetic analogues
• Tubocurarine binds motor end plate receptors blocking the nicotinic ACh receptor action of ACh

Question 3

Tubocurarine and atracurium

Answer 3

• We don’t need to remember to structures but we do need to identify the sections of the drugs and compare them to the receptors (or chemical that works at the receptor)
• Atracurium has the ester bond- same as ACh- also has 2 of them which increases its potency
• Tubocurarine has the positive N group which is the same as ACh and also has 2 of them meaning it is a potent binder

Question 4

Hyoscine and Atropine

Answer 4

• 2 plants commonly used to dispatch unwanted ‘guests’ were henbane (Hyoscyamus niger ) and deadly nightshade (Atropa belladonna)
• All members of solenaca, which includes tomatoes, potatoes but also Mandrake and Datura
• Henbane and deadly nightshade used in low doses as hallucinogens, and as medicines by the early pharmacist
• The main constituent of belladonna is atropine, and of henbane is hyoscine (Scopolamine) tropane alkaloids
• Datura responsible for many accidental deaths of explorers and settlers but smoked by ancient Egyptians to relieve a toothache, and even sold in herbal cigarettes in Spain (19th.C) as having ‘sedative’ properties
• In ancient Greece and Rome henbane used to induce trance-like states associated with prophecy

Question 5

Hyoscine and atropine

Answer 5

• Atropa belladonna, Hyoscyamus niger and mandragora officianarum main constituents of the original ‘witch brew’
• Mixed with fat forms a salve that allows adsorption through the skin
• Block the muscarinic ACh receptor selectively
• Atropine isolated in 1831 and started to be used in ophthalmology in 1902 hyoscine began to be used as a premed in 1910
• Ipratropium is a synthetic analogue used in the treatment of asthma by inhalation- causes muscles to relax- has the positive charged nitrogen- same as tubocurarine

Question 6

Esere

Answer 6

• Many toxic plants used in trial by ordeal
• Physostigma venenosa- Calabar bean. Like many others, the effects first describes by missionaries- Physostigmine
• The extract called Esere used in West Africa for trial by ordeal and executions
• Medical studies led by Robert Christison in the 1850s- found esere blocked heart muscle rather than the respiratory system
• Thomas Fraser noted that putting esere in the eye caused a contraction of the pupil and copious tear production (use as a treatment for glaucoma)- the opposite to atropine, and demonstrated it could counter its effects
• Further studies lead to the identification of physostigmine as an active component, and directly to the discovery of ACh as a nerve transmitter and the role of AChE (blocked by the drug)
• Still used to treat myasthenia gravis, glaucoma and Alzheimers

Question 7

Physostigmine

Answer 7

• Acetylcholinesterase inhibitor
• Binds covalently to the acetylcholineesterase
• Slowly hydrolysed (hours)]
• Physiostigmine is an AChE inhibitor- meaning that ACh doesn’t get broken down so muscle stays contracted
• This lead to the discovery of AChE
• MUST BE ABLE TO DRAW ACh

Question 8

Toxic mushrooms

Answer 8

• Amanita Muscarina- trace amount of muscarine (ACh) but ibotenic acid (NMDA) and muscimol (GABA) active components
• Amanita phalloides- death cap mushroom
• Amanita species responsible for 95% poisoning
• Amanitins block RNA Po III, phalloidin F-actin polymerization
• Effects have a slow onset
• That is muscarine- has a Quaternary ammonium group (Positive N) = mimic ACh cause contraction
• ibotenic acid- act at NMDA (responsible for thought process)= hallucinations
• Phalloidin= stains cells very important

Question 9

Ergotamine- origin

Answer 9

• Fungal toxins have been noted for many years
• Claviceps purpurea one of histories biggest kills- also known as ergot (first recorded 600 BC)
• Produces ‘ergot alkaloids’ such as ergotamine
• Contaminated bread made from infected rye- causes loss of blood flow to extremities- St.Anthony’s fire- leads to gangrene
• Vasoconstrictive properties exploited in the treatment of post-partum bleeding (and abortion). Also noted the hallucinogenic effect
• Studies by Hofmann led to the partially accidental discovery of further drugs
• Ergotamine can mimic action of seratonin (6 membered ring,5 membered pyrole with N ring- with an amine)

Question 10

Ergotamine

Answer 10

• Synthesized in serotonergic neurons of the CNS
• Regulation of mood, appetite and sleep
• Some cognitive functions: memory and learning
• Modulation of serotonin at synapses by pharmacological antidepressants
• LSD binds 5-HT_2A receptors
• Both LSD AND ERGOTAMINE contain 5-Hydroxytrypamine

Question 11

Relative toxicity

Answer 11

Question 12

Penicillin

Answer 12

• 1929 Alexander Flemming reported the observation of the lysis of Staphylcoccus by a contaminating mould
• He demonstrated this was a more general effect on streptococci, staphylococci, pneumococci, meningococci, gonococci and diphtheria bacilli, identified the mould a penicillium and demonstrated its used to clear pneumococcal conunctivitis
• He then gave a really bad talk about the work and as there had been similar reports before and lysozyme was being studied in more depth no on took any notice
• Howard Florey- moved to Oxford and went on the hunt for antibiotics, rediscovered the penicillium story, but was better able to isolate the unstable antibiotic
• Development of PenV and then discovery of cephalosporins

Question 13

Microbial screening

Answer 13

• Grow micro-organisms isolated from the environment
• Screen for an activity of interest
• Purify active components using the activity as a marker
• Lead for drug discovery
• Thought that <5% of organisms can be cultured in the laboratory
• Isolating and identifying the active can be very time consuming
• Turning a natural product into a drug can be difficult

Question 14

Important compounds

Answer 14

Question 15

Examples of steroid hormone derived from cholesterol

Answer 15

• tetracyclic core ring system (6,6,6,5 ring system)
• Fixed system-functional groups are held in place (like scaffholiding)
• Small, simple changes have large, significant effects
• Progesterone is semi-synthetic (made from ergosterol)
• Osterone synthesised from ChE from mycobacterium

Question 16

3D structure of steroid

Answer 16