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MPharm 2 - PH2114 > Stereochemistry 1 > Flashcards

Stereochemistry 1 Flashcards

1
Q

What does R/S describe in chiral centres?

A

Classifies a chiral centre by the groups around it
One of the pair is R
The other one of the pair is S

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2
Q

What does D/L describe in chiral centres?

A

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

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3
Q

What does d/l (or +/-) describe in a chiral molecule?

A

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

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4
Q

What percentage of drugs are administered as a mixture?

A

25%

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5
Q

What are enantiomers?

A

A pair of stereoisomers that are non-identical mirror images of each other

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6
Q

What are diastereoisomers?

A

A pair of non-identical stereoisomers that are not mirror images of each other

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7
Q

What is a meso compound?

A

A non-optically active stereoisomer

- containing a plane of symmetry

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8
Q

What are important drug targets?

A

Proteins

  • enzymes
  • receptors
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9
Q

Why are proteins highly chiral environments?

A

They are built from amino acids

- 19/20 contain at least one chiral centre

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10
Q

What are thalidomide and lenalidomide currently used for?

A

Bone marrow cancer

- myeloma

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11
Q

What safety precaution must be taken when using thalidomide or lenalidomide?

A

Female patients MUST comply with a pregnancy prevention programme

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12
Q

How are molecules containing a chiral centre prepared easily?

A

As a racemic mixture

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13
Q

What is it very difficult to separate a racemic mixture into?

A

Single enantiomers

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14
Q

How can a pure chiral molecule be obtained?

A

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.

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15
Q

How does chiral separation work?

A

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

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16
Q

What is the disadvantage of alternative methods to chiral separation e.g selective crystallisation?

A

They are all wasteful

- 50% of material is thrown away

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17
Q

How can biosynthesis be used to produce one single enantiomer?

A

Synthesis of molecules by a biological organism is often steroselective
- one enantiomer formed in preference to another

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18
Q

How is noradrenaline biosynthesised stereoselectively?

A

Noradrenaline is biosynthesied stereoselectively from dopamine by the enzyme dopamine beta-hydroxylase

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19
Q

Why are biochemicals frequently produced as single enantiomers?

A

Enzymes mediate biosynthesis of endogenous molecules

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20
Q

What is carvone?

A

A plant derived terpene natural product

- plants often produce a single stereoisomeric molecule

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21
Q

How can our noses distinguish between enantiomers of carvone?

A

R - spearmint

S - caraway

22
Q

Why can our noses detect different enantiomers of a molecule?

A

Our sense of smell is governed by olfactory receptors
- proteins
- chiral!
Each enantiomer binds to a different receptor

23
Q

What is the chiral pool?

A

Chiral molecules from nature that can be used as useful building blocks

24
Q

Why is Tamiflu difficult to make?

A

It has three chiral centres

25
Q

How is Tamiflu made?

A

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
26
Q

Give two examples of drugs that are given as racemic mixtures

A

Warfarin
- anticoagulant
Ketoprofen
- NSAID

27
Q

Give examples of drugs that are given as a single enantiomer

A

DEXTROmethorphan

LEVOthyroxine

28
Q

What is a eutomer?

A

An isomer with the greater activity

29
Q

What is a distomer?

A

An isomer with the lower activity

30
Q

What is the eudismic ratio?

A

The ratio between the eutomer and the distomer

31
Q

Which propranolol isomer is the eutomer?

A

Propanolol is given as a racemic mixture
- a significant proportion of the dose is inactive!

R = distomer
S = eutomer
32
Q

How many chiral centres does promethazine have?

A

One

- both enantiomers have similar activity (and side effects)

33
Q

What is the difference between dextromethorphan and levomethorphan?

A 
Dextromethorphan
- widely used antitussive
- virtually no side effects
Levomethorphan
- anti-tussive
- all the effects of an opiod
- analgesia
- sedative
- severe addition
- NOT MARKETED!
34
Q

in a pair of stereoisomers which is the distomer and which is the eutomer ?

A

For a pair of stereoisomers:
The isomer with the greater activity is the eutomer.
The isomer with lower activity is the distomer

35
Q

How do different isomers effect ADME ?

A

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.

36
Q

Why can exploiting chirality in drug design save money?

A

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

37
Q

What is the chiral switch?

A

The development of a single isomer drug from a previously marketed racemate

38
Q

What is dexibuprofen?

A

The dextrorotatory (they just happen to be both S-isomers using the R/S system) enantiomer of ibuprofen

39
Q

What are the advantages of the chiral switch?

A 
Improved biological activity
Modified dosage
More selective
- no off target binding
Reduced side effects
Simpler pharmacokinetics
Opportunity to market a new product
40
Q

Which enzyme is inhibited by S-isomer of ibuprofen?

A

Cyclooxygenase

41
Q

What percentage of the R-isomer of ibuprofen, which is inactive, is converted to the S-isomer?

A

60%

42
Q

How much more effective is dexibuprofen compared to ibuprofen?

A

Clinical trials established that dexibuprofen was as effective as ibuprofen at half the dose

43
Q

What is dexibuprofen marketed as?

A

Seractil (POM) for

  • pain
  • inflammation
  • osteoarthritis
  • dysmenorrhoea
  • dental pain
44
Q

Which well tolerated antihistamine is administered as a racemate?

A

Cetirizine

45
Q

What is the target of cetirizine antihistamine?

A

H1 histamine receptor

46
Q

Which isomer of cetirizine binds to the H1 receptor?

A

The R isomer binds to the H1 receptor
- levorotatory
The S isomer is inactive

47
Q

What is the drug of choice for spinal anaesthesia?

A

Bupivacaine

- local anaesthetic derived from lidocaine

48
Q

What are the side effects of Bupivacaine?

A

Cardiovascular side effects

49
Q

How do both enantiomers of Bupivacaine work?

A

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

50
Q

Why is S-Bupivacaine used for spinal anaesthetic?

A

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

MPharm 2 - PH2114 (32 decks)

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