Stereochemistry 1 Flashcards
What does R/S describe in chiral centres?
Classifies a chiral centre by the groups around it
One of the pair is R
The other one of the pair is S
What does D/L describe in chiral centres?
Classifies a chiral centre by comparison to a reference compound
- glyceraldehyde
group goes right its D
The other one of the pair is L
dunno how to explain it
What does d/l (or +/-) describe in a chiral molecule?
Classifies a molecule but the direction that it rotates polarised light
d or + = dextrorotatory (clockwise)
l or - = levorotatory
(anticlockwise)
d/l rarely used due to confusion with D/L
+/- used in preference
What percentage of drugs are administered as a mixture?
25%
What are enantiomers?
A pair of stereoisomers that are non-identical mirror images of each other
What are diastereoisomers?
A pair of non-identical stereoisomers that are not mirror images of each other
What is a meso compound?
A non-optically active stereoisomer
- containing a plane of symmetry
What are important drug targets?
Proteins
- enzymes
- receptors
Why are proteins highly chiral environments?
They are built from amino acids
- 19/20 contain at least one chiral centre
What are thalidomide and lenalidomide currently used for?
Bone marrow cancer
- myeloma
What safety precaution must be taken when using thalidomide or lenalidomide?
Female patients MUST comply with a pregnancy prevention programme
How are molecules containing a chiral centre prepared easily?
As a racemic mixture
What is it very difficult to separate a racemic mixture into?
Single enantiomers
How can a pure chiral molecule be obtained?
Two practical approaches to obtaining pure chiral molecules are:
Chiral Separation: use a physical method, e.g. chromatography, to
separate the desired stereoisomer from a mixture
The Chiral Pool: Use a starting material that already contains a
chiral centre.
How does chiral separation work?
Chromatography (HPLC) can be used to separate a mixture of racemic isomers to single stereoisomers using a chiral stationary phase
Impractical on a large scale
- e.g. manufacturing a drug
What is the disadvantage of alternative methods to chiral separation e.g selective crystallisation?
They are all wasteful
- 50% of material is thrown away
How can biosynthesis be used to produce one single enantiomer?
Synthesis of molecules by a biological organism is often steroselective
- one enantiomer formed in preference to another
How is noradrenaline biosynthesised stereoselectively?
Noradrenaline is biosynthesied stereoselectively from dopamine by the enzyme dopamine beta-hydroxylase
Why are biochemicals frequently produced as single enantiomers?
Enzymes mediate biosynthesis of endogenous molecules
What is carvone?
A plant derived terpene natural product
- plants often produce a single stereoisomeric molecule
How can our noses distinguish between enantiomers of carvone?
R - spearmint
S - caraway
Why can our noses detect different enantiomers of a molecule?
Our sense of smell is governed by olfactory receptors
- proteins
- chiral!
Each enantiomer binds to a different receptor
What is the chiral pool?
Chiral molecules from nature that can be used as useful building blocks
Why is Tamiflu difficult to make?
It has three chiral centres
How is Tamiflu made?
The industrial method starts from shikimic acid
- a natural product isolated from the Chinese herb Star Anise
- important starting material as it naturally contains three chiral centres that can be manipulated
Give two examples of drugs that are given as racemic mixtures
Warfarin
- anticoagulant
Ketoprofen
- NSAID
Give examples of drugs that are given as a single enantiomer
DEXTROmethorphan
LEVOthyroxine
What is a eutomer?
An isomer with the greater activity
What is a distomer?
An isomer with the lower activity
What is the eudismic ratio?
The ratio between the eutomer and the distomer
Which propranolol isomer is the eutomer?
Propanolol is given as a racemic mixture
- a significant proportion of the dose is inactive!
R = distomer S = eutomer
How many chiral centres does promethazine have?
One
- both enantiomers have similar activity (and side effects)
What is the difference between dextromethorphan and levomethorphan?
Dextromethorphan - widely used antitussive - virtually no side effects Levomethorphan - anti-tussive - all the effects of an opiod - analgesia - sedative - severe addition - NOT MARKETED!
in a pair of stereoisomers which is the distomer and which is the eutomer ?
For a pair of stereoisomers:
The isomer with the greater activity is the eutomer.
The isomer with lower activity is the distomer
How do different isomers effect ADME ?
Distribution. Most drugs are transported in the blood by reversible binding to plasma proteins, e.g. human serum albumin. Different stereoisomers will bind with different affinities (the effect is often small).
Metabolism. Different stereoisomers can be metabolized differently
Excretion. Less extensively studied. Some research has shown that S-enantiomers of some NSAIDS have 2-3-fold differences in renal clearance.
Why can exploiting chirality in drug design save money?
The cost of developing a drug is very high
- £1 billion +
It takes a long time to develop a drug
- ~20 years
A significant number of commercial successful drugs are administered as racemates
The chiral switch achieves novelty by preparing and marketing the single enantiomer
- cheaper
- quicker
- much of the previous development has already been done
What is the chiral switch?
The development of a single isomer drug from a previously marketed racemate
What is dexibuprofen?
The dextrorotatory (they just happen to be both S-isomers using the R/S system) enantiomer of ibuprofen
What are the advantages of the chiral switch?
Improved biological activity Modified dosage More selective - no off target binding Reduced side effects Simpler pharmacokinetics Opportunity to market a new product
Which enzyme is inhibited by S-isomer of ibuprofen?
Cyclooxygenase
What percentage of the R-isomer of ibuprofen, which is inactive, is converted to the S-isomer?
60%
How much more effective is dexibuprofen compared to ibuprofen?
Clinical trials established that dexibuprofen was as effective as ibuprofen at half the dose
What is dexibuprofen marketed as?
Seractil (POM) for
- pain
- inflammation
- osteoarthritis
- dysmenorrhoea
- dental pain
Which well tolerated antihistamine is administered as a racemate?
Cetirizine
What is the target of cetirizine antihistamine?
H1 histamine receptor
Which isomer of cetirizine binds to the H1 receptor?
The R isomer binds to the H1 receptor
- levorotatory
The S isomer is inactive
What is the drug of choice for spinal anaesthesia?
Bupivacaine
- local anaesthetic derived from lidocaine
What are the side effects of Bupivacaine?
Cardiovascular side effects
How do both enantiomers of Bupivacaine work?
Block sodium and potassium ion channels
R-Bupivacaine is slightly more active, but also causes cardiotoxicity.
Clinical trials established that although less active, the same sensory block could be achieved with S-bupivacaine compared to the racemate
Why is S-Bupivacaine used for spinal anaesthetic?
Clinical trials established that although less active, the same sensory block could be achieved S-Bupivacaine compared to the racemate
Levobupivacaine has anaesthetic and analgesic properties similar to Bupivacaine but is thought to have fewer adverse effects
