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Medicinal Chemistry > Lecture 3 - Drug Absorption/Isomers > Flashcards

Lecture 3 - Drug Absorption/Isomers Flashcards

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1
Q

What does the size of a molecule and its number of freely rotatable bonds effect?

A
  • Activity
  • Absorption
  • Distribution
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2
Q

What are rotatable bonds?

A

Any single bond that is:

  • not part of a ring
  • not formed w/ a terminal atom
  • not formed w/ an H atom
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3
Q

Are amide C-N bonds freely rotatable and why?

A

No b/c of resonance

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4
Q

Are amide enol keto tautomers freely rotatable and why?

A

No b/c of resonance

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5
Q

What do rotatable bonds have to do with crossing a membrane?

A

Usually a drug will have to be in a single conformation to cross a membrane

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6
Q

What do rotatable bonds have to do with binding to a receptor?

A

Usually drugs adopt one or a few conformations to bind to a receptor or transporter

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7
Q

What does more conformational freedom mean?

A

Less time spent in the right conformation for optimal absorption or binding

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8
Q

How do molecules w/ many freely rotatable bonds adopt a single conformation?

A

Must drop entropy significantly

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9
Q

What is Lipinski’s rule of fives?

A

A series of guidelines that determine if a drug can be absorbed orally

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10
Q

What are the rules of Lipinski’s rule of fives?

A

1) Molecular weight > 500
2) logP < 5
3) < 5 H-bond donors (sum of NH and OH)
4) < 10 H-bond acceptors (sum of lone pairs on N and O)
5) < 10 rotatable bonds

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11
Q

What can be concluded about polar drugs that don’t follow Lipinski’s rules?

A
  • Not orally absorbed

- May be made into an injectable dosage form

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12
Q

What were Lipinski’s rules originally intended for and what are they used for now?

A
  • Originally intended to be a way of predicting oral absorption
  • Now used as a guide for industry to select candidate drugs
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13
Q

Does Lipinski’s rule of fives dictate pharmacologic activity?

A

Nope

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14
Q

What can be concluded about drugs on the market that don’t follow Lipinski’s rules?

A

They are taken up by transporters or other methods

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15
Q

Do all isomers have biological activity and why?

A

No, because normally only one configuration will bind to a receptor

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16
Q

Do all isomers have the same potency and toxicity?

A

No

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17
Q

Are all isomers metabolized the same?

A

No

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18
Q

Do isomers have the same molecular weight?

A

Yes

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19
Q

What are the 3 types of isomers?

A

1) Constitutional/structural/positional
2) Configurational
3) Conformational

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20
Q

What are constitutional isomers?

A

Have the same atomic composition but different bonding arrangements between atoms (ex: ortho, meta, para)

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21
Q

What are configurational isomers?

A

Have the same molecular formula and same bonds but the atoms are arranged differently in space with respect to each other

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22
Q

Can configurational isomers interconvert freely by bond rotation?

A

No

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23
Q

What are the 2 types of configurational isomers?

A

Optical and geometric

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24
Q

What are conformational isomers?

A

Different arrangements of atoms that result from rotation about sigma bonds

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25
Q

Can conformational isomers interconvert between isomeric forms?

A

Yes

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26
Q

When 4 different groups are bound to a carbon, how many distinct tetrahedral molecular forms (optical isomers) are possible?

A

2

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27
Q

What is another name for optical isomers?

A

Enantiomers

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28
Q

How many asymmetric centres can enantiomers have?

A

1 or more

29
Q

Do enantiomers have identical physical and chemical properties?

A

Yes

30
Q

What are the 2 important differences between enantiomers?

A
  • Rotation of plane-polarized light

- Interaction w/ chiral environments

31
Q

What does dextrorotatory mean?

A

Enantiomer rotates the plane to the right (clockwise)

32
Q

What does levorotatory mean?

A

Enantiomer rotates the plane to the left (counterclockwise)

33
Q

Can you determine the rotation of plane polarized light by inspection of a molecule’s structure?

A

No, it must be determined experimentally

34
Q

Can you determine the configuration of atoms around an asymmetric carbon from the direction of rotation?

A

No

35
Q

What is a racemic mixture?

A

A 50/50 mixture of each enantiomer

36
Q

Do racemic mixtures rotate plane-polarized light?

A

No

37
Q

Is it easier to produce a racemic mixture or a pure enantiomer?

A

Racemic mixture

38
Q

For “n” asymmetric centres, how many configurational isomers are possible?

A

Up to 2^n

39
Q

What are diastereomers?

A

Compounds w/ more than 1 asymmetric centre where the compounds are not mirror images and are not superimposable

40
Q

What are meso structures?

A

2 structures with 2 identical asymmetric centres such that the mirror images are superimposable

41
Q

Are meso structures chiral?

A

No

42
Q

Do meso structures have a plane of symmetry?

A

Yes

43
Q

Will both enantiomers of a drug bind to a receptor or enzyme?

A

Not usually

44
Q

All amino acids are ___

A

L

45
Q

What do D and L indicate?

A

Absolute configuration around an asymmetric carbon

46
Q

Do D and L tell you anything about rotation of plane-polarized light?

A

No

47
Q

How do you determine if an amino acid is D or L?

A

Whether the alpha H points left or right when the COOH group is up and NH2 is down

48
Q

Structures of enantiomers are designated as ___ or ___

A

R or S

49
Q

What are the steps to determine if an enantiomer is R or S?

A
  • Give each group directly attached to the asymmetric carbon a priority based on atomic number
    • When 2 directly attached atoms have the same priority, move to the next atom out to assign priority
    • If a double bond is present, the attached double bond atom is counted twice
  • Once all are assigned a priority, the lowest priority group is turned into the page
  • An ark is drawn connecting the groups facing out from highest to lowest
    • Clockwise = R; counterclockwise = S
50
Q

Do R and S determine if an atom is d or l?

A

No

51
Q

Are all amino acids either R or S?

A

Can be either

52
Q

What does erythro mean?

A

When all H’s in a Fischer projection point in the same direction

53
Q

What does threo mean?

A

When the H’s in a Fischer projection point in opposite directions

54
Q

Can alkenes have geometric isomers?

A

Yes, if each carbon in the double bond has different substitutions

55
Q

Is rotation around a double bond possible?

A

No

56
Q

Do geometric isomers have the same chemical properties?

A

No

57
Q

What do E and Z mean?

A

E = trans and Z = cis

58
Q

How do you determine E and Z?

A

Priority is assigned to substituents on either carbon of a double bond, if the higher priority groups are on the same side it is Z and opposite sides is E

59
Q

Are the bonds in a ring system always cis?

A

No, can be trans

60
Q

Is eclipsed or staggered form higher energy?

A

Eclipsed

61
Q

Is eclipsed or staggered form favoured and why?

A

Staggered because it is low energy

62
Q

Do cyclohexane have any pi bonds?

A

No, all sigma

63
Q

Why is the boat conformation less favourable?

A

It is in the fully eclipsed conformation

64
Q

Why is the chair conformation more favourable?

A

It is staggered

65
Q

Is cyclohexane always in the chair conformation?

A

No, inter-conversion between chair and boat is possible

66
Q

What is favoured with respect to equatorial and axial substitutions?

A
  • 2 equatorial substitutions of H to CH3 is more stable and favoured
  • 1 equatorial and 1 axial substitution is less stable and not favoured
67
Q

For substituted cyclohexanes, which is the most stable?

A

The one with the greatest number of equatorial groups

68
Q

For cyclohexanes with bulky substitutions, which conformation is most favourable?

A

The one that allows the substitution to be equatorial

Medicinal Chemistry (14 decks)

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