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DDD x > Week 4 Part 2 > Flashcards

Week 4 Part 2 Flashcards

1
Q

What are examples of single-enantiomer drugs?

A
  1. Lipitor (atorvastatin calcium)
  2. Plavix (clopidogrel bisulphate)
  3. Nexium (esomeprazole magnesium)
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2
Q

What is the total sales of single-enantiomer drugs ?

A

$30 billion

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3
Q

Mirror image of the drug

A

Not going to interact with the protein target

Biologically inactive or less active

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4
Q

Many biological targets

A

Going to be drug-specific in their interactions

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5
Q

What can isomers be divided into?

A
  1. Constitutional/structural isomers

2. Stereoisomers

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6
Q

What are stereoisomers divided into?

A
  1. Configurational isomers

2. Conformational isomers

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7
Q

What can conformation isomers of stereoisomers be divided into?

A
  1. Rotamers
  2. Atropisomers
  3. Ring inversion isomers
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8
Q

What can configurational isomers of stereoisomers be divided into?

A
  1. Diastereomers

2. Enantiomers

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9
Q

What can Diastereomers be divided into?

A
  1. Cis/trans-isomers

2. Diastereomers containing a chiral centre

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10
Q

Define isomers

A

Different compounds with same chemical formula

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11
Q

Constitutional isomers

A

Very little relevance to us

Same chemical constitution and they can be different molecules

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12
Q

What does isomers have?

A
  1. Same functional groups

2. Different physical and chemical properties

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13
Q

What can stereoisomers be separated into?

A
  1. Diastereomers

2. Enantiomers

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14
Q

Why are Diastereomers very common in chemistry?

A

Same chemical groups

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15
Q

Define stereoisomers

A

Compounds with the same chemical group connections

Different arrangement in space

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16
Q

Define Diastereomers

A

Stereoisomers that are not mirror images

Different chemical compounds

Different physical properties

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17
Q

Conformers and Rotamers

A

Very little importance

Have unstable structures

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18
Q

Define Enantiomers

A

Stereoisomers that are non superimposable mirror images

Differ only in their optical activity/direction of optical rotation

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19
Q

Define chirality

A

Geometric property of some molecules where a chiral molecule is not superimposable on its mirror image

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20
Q

What creates a chiral centre?

A

Chiral carbon atom or asymmetric carbon atom that is bonded to 4 different groups creating a chiral centre

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21
Q

What are different forms of chirality called?

A

Enantiomorph

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22
Q

Enantiomorph

A

A chiral centre results in two possible structures which are mirror images of each other

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23
Q

What is optical activity?

A

The ability to rotate the plane of polarised light

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24
Q

What can chirality be described at?

A

In terms of absolute configuration which defines the geometry of the molecule and the relationship with its ability to rotate polarised light

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25
Q

What is polarineter?

A

A device or equipment for measuring the degree of rotation of polarised light and therefore the chirality of enantiomers

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26
Q

What is Racemic Mixture?

A

Equal quantities of enantiomers

No optical activity

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27
Q

What is the basic principle of polarimetry?

A
  1. Have focused polarised light in filter
  2. Shine light through sample chamber
  3. Measure the level of reflection
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28
Q

Polarimetry - rotates clockwise

A

Dextrorotatory (+ or d)

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29
Q

Polarimetry - rotates counter clockwise

A

Levorotatory (-, I)

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30
Q

What is the physicochemical properties of enantiomers?

A
  1. Same boiling point
  2. Same melting point
  3. Same density
  4. Same refractive index
  5. Rotate the plane of polarised light to the same magnitude but in opposite directions
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31
Q

What is biological discrimination?

A
  1. Active site of enzymes and receptors generally selective for a specific enantiomers
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32
Q

What are examples of biological discrimination?

A
  1. Taste buds
  2. Scent receptors

Show chiral discrimination

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33
Q

What may enantiomers have?

A

Different smells

D-limonene - citrus/orange skins

L-limonene - turpentine odour

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34
Q

The history of molecule - 1848

A

Pasteur achieves the first optical resolution of the (+) and (-) of tartaric acid

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35
Q

The history of molecule - 1891 -1900

A

Fischer Projection

A two-dimensional representation of three-dimensional organic molecules originally proposed for depiction of carbohydrates

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36
Q

The history of Molecule - 1951-1966

A

Cahn-Ingold-Prelog (CIP)

Priority rules

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37
Q

What is the limitation of Fischer Projection?

A

Doesn’t really tell you much about the structure of a molecule

38
Q

What is the Fischer Projection?

A

The penultimate group of the molecule defines whether D or L form depending on whether the hydrogen is on the left or right

39
Q

Penultimate carbon of D-sugars

A

Hydrogen in left

Hydroxyl on the right

40
Q

What does the D- and L1 nomenclature relate to?

A

Whether the hydroxyl is drawn on the right or left

41
Q

What is Fischer Projection not based on?

A

Any measure of optical activity

42
Q

What is the D- and L- system of Fischer Projection used for?

A
  1. Sugars

2. Amino acids

43
Q

Naturally occurring sugars

A

D-

44
Q

Naturally occurring amino acids

A

L-

45
Q

What is glycine?

A
  1. Achiral
46
Q

What are the 19 amino acids occurring naturally?

A

L-amino acids

47
Q

How does the CIP naming system work?

A
  1. 4 groups aroubd a chiral centre are prioritised according to atomic number. The highest atomic number is assigned priority 1 and the lowest atomic number is assigned priority 4
  2. If two or more of the atoms are attached to chiral centre are the same then outward exploration is necessary to identify the group with highest atomic number
  3. A clockwise decreasing order is assigned (R)-configurational and anti clockwise decreasing order is assigned (S)-configuration
48
Q

What is biological discrimination important for?

A

Protein-target recognition

49
Q

What is Ephedrine?

A

Natural molecule that is being used for centuries in medicine

Traced back to Chinese medicine

Sympathomimetic amine stimulates the release of noradrenaline from the sympathetic nerve terminals

Traditional use in anti-asthmatics

50
Q

What are 2 active form of isomers?

A
  1. Ephedrine

2. Pseudoephedrine

51
Q

Why was pseudoephedrine banned?

A

Causes hypertension

52
Q

What are examples of Racemic drugs with equally bioactive enantiomers?

A
  1. Anti-cancer drug e.g. cyclophosphamide

2. Antidepressant e.g. fluoxetine

53
Q

Unidirectional: what is active?

A
  1. S-ibuprofen
54
Q

What is R-ibuprofen converted into?

A

S- by hepatic enzymes

55
Q

What Racemic drug undergo chiral inversion?

A

Bidirectional:

  1. 3-hydroxybenzodiazepine

E.g. lorazepam and temazepam

56
Q

What are 3 examples which illustrate a problem in terms of using a Racemic mixture as a therapeutic product?

A
  1. Citalopram
  2. Methadone
  3. Warfarin
57
Q

What is Citalopram?

A

Antidepressant

58
Q

What is methadone used as?

A

Opioid

Provide pain relief

Main therapeutic use is to give to addict to wheel off the opioids

59
Q

Methadone

A

Reversal of addiction

Long action

60
Q

What enantiomers is the most active?

A

S-warfarin

61
Q

R(-) methadone

A

Opioid

62
Q

S (+) methadone

A

Inhibits hERG

63
Q

Potassium channel

A

Prolonged QT interval

Torsades de pointes

64
Q

What is the active isomer of citalopram?

A

Escitalopram

65
Q

What is the pharmacokinetic of stereochemistry?

A
  1. Absorption
  2. Distribution
  3. Metabolism
  4. Elimination
66
Q

What can enantiomers have?

A

Identical efficacy and toxicity

67
Q

What can one enantiomer possess?

A

Much greater pharmacological activity

68
Q

What can one enantiomer have?

A

Less pharmacological activity and similar or greater toxicological effects

69
Q

What are majority of Racemic drugs absorbed by?

A

Passive diffusion which has no stereoselectictivity

70
Q

What does plasma protein binding have a key influence on?

A
  1. Tissue distribution
  2. Pharmacological properties
  3. Merabolism/elimination
71
Q

What may enantiomers show?

A
  1. Stereoselectivity for protein binding
72
Q

R (+) propanolol

A
  1. High albumin binding
  2. High rate of metabolism
  3. Low plasma concentration
  4. Less potent as a beta-blocker
73
Q

S (-) propranolol

A
  1. Highly bound to alpha1-acid glycoprotein
  2. Slower metabolism
  3. 60-100 times more potent as a beta-blocker
74
Q

What is common?

A

Stereoselective metabolism of drugs

75
Q

Warfarin

A
  1. Exceptionally complex
  2. Affected by genetic polymorphism
  3. Wide inter-individual variation in dose response and frequent bleeds
76
Q

What is the most active enantiomer of warfarin?

A

S-warfarin

77
Q

What is S-warfarin metabolised by?

A

CYP2C9

78
Q

What is R warfarin metabolised by?

A

3 different CYPS

79
Q

How does warfarin work?

A

Inhibits the enzyme that is involved with vitamin K

Involved in changes in glutamate side chains of these coagulation factors

80
Q

What is a real risk of overdose/toxic consequence of methadone consumption?

A

Bigger concentration of opioid depressing activity and cardiotoxic metabolite

81
Q

Thalidomide

A
  1. Sold as Racemic mixture from 1957-1961
  2. Used to treat morning sickness until birth defects were known
  3. R-enantiomer is sedative (desired effect)
  4. S-enantiomer is teratogenic or the source of ateratogenic metabolite (mechanism never fully define)
  5. In Vivo conversion of R- into S- so no safe isomer
82
Q

What is Omeprazole?

A
  1. The first proton pump (H+, ATPase) inhibitor for treatment of gastric acid-related disease
  2. Primarily metabolised by polymorphically expressed cytochrome P450 - CYP2C19.1
83
Q

Esomeprazole

A

Metabolised to a lesser extent by CYP2C19 than R-Omeprazole

Metabolised at a lower rate

Higher plasma levels

84
Q

What does S-enantiomer of Omeprazole inhibit?

A

CYP2C19

85
Q

What can pure enantiomers be?

A
  1. Safe

2. More effective drugs

86
Q

What is an example of 50/50 Racemic ?

A
  1. Formoterol

2. Salmeterol

87
Q

What is the advantage of Enantiopure?

A
  1. Greater pharmacological efficacy

2. Reduced side effects

88
Q

What are the 2 main strategies for preparation of enantiopure compounds?

A
  1. Chiral Resolution

2. Asymmetric synthesis

89
Q

What is chiral resolution?

A

Synthesis as a racemate

Followed by separation of the enantiomers

90
Q

What is asymmetric synthesis?

A
  1. Use of chiral starting materials, chiral catalyst and the application of asymmetric induction
  2. Enzymes (biocatalyst) may be hard to produce the desired compound or chiral intermediate
  3. Enantioconvergent synthesis - the desired enantiomer is synthesised from a Racemic precursor molecule

DDD x (17 decks)

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