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DDD x > Week 4 Part 2 > Flashcards

Week 4 Part 2 Flashcards

(90 cards)

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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
What is polarineter?
A device or equipment for measuring the degree of rotation of polarised light and therefore the chirality of enantiomers
26
What is Racemic Mixture?
Equal quantities of enantiomers No optical activity
27
What is the basic principle of polarimetry?
1. Have focused polarised light in filter 2. Shine light through sample chamber 3. Measure the level of reflection
28
Polarimetry - rotates clockwise
Dextrorotatory (+ or d)
29
Polarimetry - rotates counter clockwise
Levorotatory (-, I)
30
What is the physicochemical properties of enantiomers?
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
31
What is biological discrimination?
1. Active site of enzymes and receptors generally selective for a specific enantiomers
32
What are examples of biological discrimination?
1. Taste buds 2. Scent receptors Show chiral discrimination
33
What may enantiomers have?
Different smells D-limonene - citrus/orange skins L-limonene - turpentine odour
34
The history of molecule - 1848
Pasteur achieves the first optical resolution of the (+) and (-) of tartaric acid
35
The history of molecule - 1891 -1900
Fischer Projection A two-dimensional representation of three-dimensional organic molecules originally proposed for depiction of carbohydrates
36
The history of Molecule - 1951-1966
Cahn-Ingold-Prelog (CIP) Priority rules
37
What is the limitation of Fischer Projection?
Doesn’t really tell you much about the structure of a molecule
38
What is the Fischer Projection?
The penultimate group of the molecule defines whether D or L form depending on whether the hydrogen is on the left or right
39
Penultimate carbon of D-sugars
Hydrogen in left | Hydroxyl on the right
40
What does the D- and L1 nomenclature relate to?
Whether the hydroxyl is drawn on the right or left
41
What is Fischer Projection not based on?
Any measure of optical activity
42
What is the D- and L- system of Fischer Projection used for?
1. Sugars | 2. Amino acids
43
Naturally occurring sugars
D-
44
Naturally occurring amino acids
L-
45
What is glycine?
1. Achiral
46
What are the 19 amino acids occurring naturally?
L-amino acids
47
How does the CIP naming system work?
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
What is biological discrimination important for?
Protein-target recognition
49
What is Ephedrine?
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
What are 2 active form of isomers?
1. Ephedrine | 2. Pseudoephedrine
51
Why was pseudoephedrine banned?
Causes hypertension
52
What are examples of Racemic drugs with equally bioactive enantiomers?
1. Anti-cancer drug e.g. cyclophosphamide | 2. Antidepressant e.g. fluoxetine
53
Unidirectional: what is active?
1. S-ibuprofen
54
What is R-ibuprofen converted into?
S- by hepatic enzymes
55
What Racemic drug undergo chiral inversion?
Bidirectional: 1. 3-hydroxybenzodiazepine E.g. lorazepam and temazepam
56
What are 3 examples which illustrate a problem in terms of using a Racemic mixture as a therapeutic product?
1. Citalopram 2. Methadone 3. Warfarin
57
What is Citalopram?
Antidepressant
58
What is methadone used as?
Opioid Provide pain relief Main therapeutic use is to give to addict to wheel off the opioids
59
Methadone
Reversal of addiction Long action
60
What enantiomers is the most active?
S-warfarin
61
R(-) methadone
Opioid
62
S (+) methadone
Inhibits hERG
63
Potassium channel
Prolonged QT interval | Torsades de pointes
64
What is the active isomer of citalopram?
Escitalopram
65
What is the pharmacokinetic of stereochemistry?
1. Absorption 2. Distribution 3. Metabolism 4. Elimination
66
What can enantiomers have?
Identical efficacy and toxicity
67
What can one enantiomer possess?
Much greater pharmacological activity
68
What can one enantiomer have?
Less pharmacological activity and similar or greater toxicological effects
69
What are majority of Racemic drugs absorbed by?
Passive diffusion which has no stereoselectictivity
70
What does plasma protein binding have a key influence on?
1. Tissue distribution 2. Pharmacological properties 3. Merabolism/elimination
71
What may enantiomers show?
1. Stereoselectivity for protein binding
72
R (+) propanolol
1. High albumin binding 2. High rate of metabolism 3. Low plasma concentration 4. Less potent as a beta-blocker
73
S (-) propranolol
1. Highly bound to alpha1-acid glycoprotein 2. Slower metabolism 3. 60-100 times more potent as a beta-blocker
74
What is common?
Stereoselective metabolism of drugs
75
Warfarin
1. Exceptionally complex 2. Affected by genetic polymorphism 3. Wide inter-individual variation in dose response and frequent bleeds
76
What is the most active enantiomer of warfarin?
S-warfarin
77
What is S-warfarin metabolised by?
CYP2C9
78
What is R warfarin metabolised by?
3 different CYPS
79
How does warfarin work?
Inhibits the enzyme that is involved with vitamin K Involved in changes in glutamate side chains of these coagulation factors
80
What is a real risk of overdose/toxic consequence of methadone consumption?
Bigger concentration of opioid depressing activity and cardiotoxic metabolite
81
Thalidomide
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
What is Omeprazole?
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
Esomeprazole
Metabolised to a lesser extent by CYP2C19 than R-Omeprazole Metabolised at a lower rate Higher plasma levels
84
What does S-enantiomer of Omeprazole inhibit?
CYP2C19
85
What can pure enantiomers be?
1. Safe | 2. More effective drugs
86
What is an example of 50/50 Racemic ?
1. Formoterol | 2. Salmeterol
87
What is the advantage of Enantiopure?
1. Greater pharmacological efficacy | 2. Reduced side effects
88
What are the 2 main strategies for preparation of enantiopure compounds?
1. Chiral Resolution | 2. Asymmetric synthesis
89
What is chiral resolution?
Synthesis as a racemate | Followed by separation of the enantiomers
90
What is asymmetric synthesis?
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

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