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Pharmacology and Medical Chemistry I > Exam 1 - Lecture 5 - 9, Organic functional groups and drug metabolism > Flashcards

Exam 1 - Lecture 5 - 9, Organic functional groups and drug metabolism Flashcards

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1
Q

Lipinski’s Rule of Five

A

orally active drug has no more than 1 violation of the following criteria

Not more than 5 HBD

Not more than 10 HBA

Molecular weight under 500 g/mol

Partition coefficient log P less than 5, 3-4 is optimal

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2
Q

rank Intramolecular forces between drug and binding site

A

Covalent (strongest, 200 - 400kJ) irreversible
Electrostatic or Ionic ( 20 - 40 kJ)
Hydrogen bonds ( 16 - 30 kJ)
Van Der Waals (2 - 4 kJ)

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3
Q

Characteristics of Electrostatic or ionic bond

A

Takes place between 2 opposite charge groups

Strong interactions in Hydrophilic environment

Strength inversely proportional to distance, drops off less rapidly than other forms

Most important initial interaction as drug enters binding site

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4
Q

Characteristics of Hydrogen Bonds

A

Between deficient hydrogen and electron rich heteroatom (N or O)

optimum orientation where angle between X,H and Y is 180

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5
Q

H-Bond donor

A

Group with electron deficient hydrogen

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6
Q

H-Bond acceptor

A

Group with electron rich heteroatom

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7
Q

Strong hydrogen bond acceptors

A

carboxylate ion, phosphate ion, tertiary amine

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8
Q

Moderate hydrogen bond acceptors

A

Carboxylic acid, amide oxygen, ketone, ester, ether, alcohol

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9
Q

Poor hydrogen bond acceptors

A

Sulfur, fluorine, chlorine, aromatic ring, amide nitrogen,, aromatic amine

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10
Q

Good Hydrogen bond donor

A

Quaternary ammonium ion

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11
Q

Characteristics of Van Der Waals interaction

A

occur between hydrophobic region of drug and target

interactions drop off rapidly with distance, crucial contribution to binding

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12
Q

Functional groups that exhibit Van Der Waals

A

Alkanes
Aromatic Hydrocarbons
Halogenated Hydrocarbons

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13
Q

Characteristics of Dipole-dipole interaction

A

occur if drug and binding site have dipole moments

orientation is beneficial if other binding groups are position correctly

orientation is detrimental if other binding groups are not positioned correctly

strength decreases more quickly than electrostatic but less quickly than VdW with distance

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14
Q

Io-dipole vs Dipole-dipole

A

Ion-dipole stronger

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15
Q

Functional groups that form dipole-dipole

A

Ether and amines

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16
Q

Functional groups that form ion-dipole

A

Alcohols, sulfuric acids, quaternary ammonium, phenol

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17
Q

Bronsted-Lowery Acid

A

substance capable of giving a proton, acid turned into conjugate base

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18
Q

Bronsted-Lowery Base

A

substance capable of accepting proton, base turned into conjugate acid

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19
Q

Bronsted-Lowery neutral

A

functional groups that cannot give up or accept a proton

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20
Q

Hydrophobic and lipophilic

A

Water hating and lipid loving

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21
Q

Hydrophilic and lipophobic

A

Water loving and lipid hating

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22
Q

Lipophilic functional groups

A

Aromatic hydrocarbons, Halogenated Hydrocarbons, Thioethers, Alkanes, Alkenes

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23
Q

Hydrophilic functional groups

A

Alcohols, carboxylic acids, amines

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24
Q

Characteristics of alkane functional groups

A

They are lipophilic

Can only do Van Der Waals

Immisicble in water, but will dissolve in lipid solvent or oil layer

Inert to conditions “on the shelf”, bc hard to oxidize C-H bond under atmospheric conditions

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25
Q

Metabolism of Alkane

A

Relatively nonreactive, excreted from body unchanged

Exception is oxidation of w-1 carbon by CYP450 (adding of OH)

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26
Q

Characteristics of alkene functional groups

A

Lipophilic and hydrophobic, dissolve well in non polar solvents

Geometric isomers possible, cis = same side…trans = opposite side

No hydrogen bonding

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27
Q

Alkene stability to “on the shelf” conditons

A

Lower members gaseous at room them, higher members liquids (more carbons = stronger bonds from VdW interactions)

Prone to oxidation in presence of oxygen, forming peroxide which is explosive

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28
Q

Metabolism of Alkene

A

Hydration, epoxidation, peroxidation and reduction

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29
Q

Characteristics of cycloalkane group

A

Chemically inert like alkanes, lipid soluble and quite flammable

No free rotation around C-C bonds, isomers possible

Hint: 1,2 diaxial is trans; 1,2 diequatorial is also trans; 1,2 axial-equatoral/equatorial-axial is cis.

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30
Q

Aromatic Hydrocarbons characteristics

A

lipophilic, flammable….formation of peroxides not a problem

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31
Q

Aromatic Hydrocarbons possible interactions

A

Ion induce dipole

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32
Q

Aromatic Hydrocarbons shelf stability

A

stable, won’t undergo aromatic hydroxylation

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33
Q

Aromatic Hydrocarbons in vivo metabolism

A

aromatic hydroxylation

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34
Q

Aromatic Hydrocarbons (Aromatic Hydroxylation)

A
  1. involves initial epoxidation
  2. Intermediate epoxides toxic, responsible for carcinogenic effect
  3. Mediated by several CYP450 isoforms
  4. Phase I reaction, significantly improves solubility

Para position preferred, least hindered and easiest to attack

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35
Q

Aromatic Hydrocarbons ( what conjugate reaction aromatic-OH undergo)

A

Sulfation or glucuronidation

becomes more water soluble

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36
Q

Enzyme involved in glucuronidation

A

UDP - glucuronyltransferase

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37
Q

Cofactor involved in glucuronidation

A

UDPGA, Uridine - 5’-diphospho-a-d–glucuronic acid

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38
Q

Enzyme involved in sulfation

A

sulfotransferases

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39
Q

Cofactor involved in sulfation

A

PAPS (3’-phosphoadenosine-5’phosphosulfate)

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40
Q

Aromatic Hydrocarbons (how to make aromatic-OH more non-polar)

A

It can undergo methylation

Enzyme: Family of O,N,S- methyltransferases

Cofactor:S-adenosyl-L-methionine (SAM)

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41
Q

Halogenated hydrocarbons characteristics

A

long half lives/ biosphere of hydrogen

increase hydrophobicity and lipophilicity of the molecule

can only do VdW

shelf stable

Not metabolized in vivo, this significant increases potential for human toxicity

not readily excreted by the kidneys

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42
Q

Binding possible between alcohol groups and target binding site

A

Strong H-bonding, utilization of intermolecular and intramolecular forces

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43
Q

Characteristics of Alcohol groups

A

cause hydrophilicity

readily metabolized in body

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44
Q

Primary alcohol oxidized into

A

aldehydes and then acids

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45
Q

Secondary alcohol oxidized into

A

Ketones

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46
Q

Enzymes involved in alcohol oxidation

A

Cytochrome P450 and alcohol dehydrogenase

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47
Q

Can alcohol form Phase II metabolites?

A

yes, glucuronide or sulfate conjugates

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48
Q

What is unique about tertiary alcohol

A

stable to oxidase enzymes, won’t undergo oxidation

Misoprostol, tertiary alcohol incorporated to prevent oxidation

49
Q

Phenol positioning

A

R
Ortho
Meta
Para

50
Q

Is phenol acidic?

A

mildy acidic due to ability to lose H atom and phenol ate stabilized by resonance, weak acid

51
Q

pKa and acidity

A

The higher the Ka, the lower the pKa

Low pKa = strong acid

52
Q

EDG effect on acidity

A

destabilize structure and decrease acidity

53
Q

EWG effect on acidity

A

stabilize structure and increase acidity

54
Q

How to make water-soluble formulation of phenol?

A

treat with strong base like Na or K hydroxide to produce a salt

55
Q

If phenol treated with sodium bicarbonate?

A

Nothing, won’t react with weak base

56
Q

What happen if sodium phenolate (salt) treated with strong acid

A

reverts back to phenol

57
Q

Phenol air stable?

A

no, undergo oxidation and form quinones (para or ortho only)

58
Q

Metabolites formed from phenol oxidation

A

Quinones, they are highly colored

59
Q

How to prevent oxidation of phenol?

A

store in amber container, or add antioxidant

60
Q

Phenolic-OH group during in vivo metabolism becomes

A

oxidized or hydroxylated

61
Q

More soluble metabolites of phenol

A

glucuronide
Sulfate conjugate
Hydroxylation, adding another OH

62
Q

Less soluble metabolites of phenol

A

methyl ether

63
Q

Physical-chemical properties of ether

A

low boiling point and poor water solubility

64
Q

Ether water solubility

A

less water soluble than alcohol due to weak h-bonding since no OH groups

65
Q

Interaction ether do at binding sites

A

Van der Waals interaction

66
Q

Ethers polar or non polar?

A

slightly polar

67
Q

What happens to ether solubility when add alkyl groups

A

significantly decreased

68
Q

Are ethers stable to on the shelf conditions

A

relatively stable and non-reactive

one exceptions, liquid ethers in contact with atmospheric oxygen form peroxides

69
Q

How to make ether more stable?

A

add copper, prevent peroxide

70
Q

Metabolism possible with ether?

A

Metabolic dealkylation reaction

71
Q

Aldehyde and ketones polar or non polar?

A

both polar groups

72
Q

What type of interactions can aldehyde and ketones do at binding site

A

H-bond

73
Q

“Keto”

A

Double bond O, 2 ch3

74
Q

“enol”

A

double bond CH2, OH and CH3

75
Q

Ketone stability on shelf

A

relatively nonreactive

76
Q

Aldehyde stability on shelf

A

rapidly oxidized to corresponding acids if not protected form atmospheric oxygen

77
Q

What is hemi-acetal

A

derived from aldehyde + alcohol and acid

R,H,OH,OR1……acetal is R,H,OR1,OR1

78
Q

What is hemi-ketal

A

Derived form ketone + alcohol and acid

R,R1,OH,OR1…..ketal is R,R,OR1,OR1

79
Q

Glucuronic acid is a…

A

hemi-acetal

80
Q

Metabolism of aldehyde in body?

A

readily oxidized to form Carboxylic acids

enzymes involved: Xanthine oxidase, aldehyde oxidase, and NAD-specific aldehyde dehydrogenase

81
Q

Can aldehyde reduce in body?

A

Yes, via minor metabolic reaction to alcohol….become more soluble

82
Q

Can keto reduce in body?

A

yes, to secondary alcohol….becomes more soluble

83
Q

what happens when a,b-unsaturated group reduced in body

A

secondary alcohol is formed

this reaction is often stereoselective and one isomer is formed

84
Q

Role of amine in drug molecule

A

important in solubilizing drug as either free base or as water-soluble salt of amine

act as binding site that holds drug to specific site to promote biologic activity

85
Q

Does amine act as HBD or HBA

A

primary and secondary = HBD + HBA

tertiary = HBA

86
Q

amines Hydrogen bond strength vs -OH group

A

Weaker H-bond than alcohol

87
Q

trend of solubility for amines

A

1>2>3

88
Q

EDG effect on basicity amines

A

Increase basicity

89
Q

EWG effect on basicity amines

A

Decrease basicity

90
Q

Basicity trend of amines

A

2>3>1 when ethyl group (2 CH2CH3)

2>1>3 when methyl group

91
Q

Methylation reaction

A

Phase II

Enzymes: O,N,S-methyltransferases
Cofactor: S-adenosyl-L-methionine (SAM)

Decrease water solubility, not very common

92
Q

Acetylation reaction

A

Phase II

Enzymes: N-acetyltransferases
Cofactors: Acetyl CoA

Decrease water solubility

Fast Acetylators: clear certain drugs faster
Slow Acetylators: clear certain drugs slower

93
Q

Sulfation reaction

A

Will do: Phenols, alcohols and lesser extent 1/2 amines
Will not: Carboxylic acids

Phase II

Enzymes: sulfotransferase
Cofactors: PAPS, 3’- phosphoadenosine-5’-phosphosulfate

94
Q

Glucuronidation reaction

A

Will do: Alcohol, Phenols, 1/2 amines, carboxylic acids

Phase II

Increase solubility

Enzymes: UDP-glucuronosyl transferase
Cofactor: uridine-5’-diphospho-a-D-glucuronic acid UDPGA

95
Q

FMO

A

Flavin-containing monoxygenase

1/2 amines = turn into hydroxylamines (OH-N,R1/R2)
3 amines = turn into N-oxides (O-N-R1/2/3)

96
Q

CYP450 info

A 
Cyp = C (chrome), Y (cyto), P(protein)
450 = peak formed by absorbance of light at this wavelength

Important components: Iron-protoporphyrin, NADPH, flavin protein,molecular oxygen

need oxygen

enzymes mainly located in smooth ER of liver

97
Q

nitro group info

A

Considered polar, charged

converted into amino group in body

Hydroxylamine is toxic intermediate

98
Q

Thioethers info

A

Like ether, replace O with S

increased lipophilicity, decreased H-bonding and water solubility

metabolized into sulfides (1 O, 2 R) or sulfones (2 0, 2 R)

99
Q

Sulfonamides info

A

acidic in nature

weak acid, carboxamides are neutral

aryl sulfonamides poor water solubility

salt formation improve water solubility

100
Q

Sulfonic acid info

A

more acidic than carboxylic acids due to sulfonate

very water soluble due to strong dipole-ion interactions

101
Q

Amide info

A

More polar/water soluble than esters

Can both H-bond and accept H-bond on O and N

More stable to acid/bases, and hydrolyzing enzymes due to stabilization

Neutral in nature, weak acid/base

Metabolism involves amidases

102
Q

Enzyme involved in biotransformation of ethanol to acetic acid?

A

Acetaldehyde Dehydrogenase

Disulfiram inhibits it

103
Q

Esters and Lactones info

A

Good solubility in alcohol

Cyclic esters = lactones

less polar than alcohols, weaker H bonding and decreased water solubility

Prone to base/acid catalyzed hydrolysis so unstable in those environments…must be protected from strongly acidic/basic environment

Esterases hydrolyze esters

replace O with NH to prevent hydrolysis

104
Q

Carboxylic acid info

A

as Alkyl groups increase, solubility decrease

greater H bonding than alcohol or phenols

Good shelf stability

105
Q

Enzyme involved in biotransformation of ethanol to acetic acid?

A

Acetaldehyde Dehydrogenase

Disulfiram inhibits it

106
Q

Mevalonic acid

A

key intermediate in biosynthesis of cholesterol

107
Q

Linoleic acid

A

essential for synthesis of cell membranes

108
Q

Arachidonic acid

A

key intermediate in synthesis of prostaglandins, prostacyclin and thromboxane

109
Q

What to do if position on aromatic ring undergoing hydroxylation and making inactive?

A

replace with biosphere lie fluorine

110
Q

Quaternary ammonium salt info

A

lipophilic, water soluble and stable on shelf

111
Q

EDG effect on basicity of aromatic amines

A

increase basicity in meta or para position

112
Q

EWG effect on basicity of aromatic amines

A

decrease basicity in meta or para position

113
Q

predictable site of aromatic amine?

A

para

114
Q

how to make aromatic amine more water-soluble

A

adding an acid to make salt

115
Q

can 3 amine undergo conjugation (Phase II)?

A

no, due to hindrance

116
Q

what metabolism convert amine group to non-polar group

A

Methylation

117
Q

requirement for deamination of 1 amine?

A

carbon attached to N must have at least 1 H

118
Q

1 amine deamination

A

cofactor: pyridoxal-5-phosphate to form pyridoxine
enzyme: MAO and DAO

119
Q

Metabolism of amines

A 
2/3 = dealkylation
1 = deamination

2/1 can undergo conjugation (Phase II)

Pharmacology and Medical Chemistry I (30 decks)

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