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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

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
Metabolism of Alkane
Relatively nonreactive, excreted from body unchanged Exception is oxidation of w-1 carbon by CYP450 (adding of OH)
26
Characteristics of alkene functional groups
Lipophilic and hydrophobic, dissolve well in non polar solvents Geometric isomers possible, cis = same side...trans = opposite side No hydrogen bonding
27
Alkene stability to "on the shelf" conditons
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
28
Metabolism of Alkene
Hydration, epoxidation, peroxidation and reduction
29
Characteristics of cycloalkane group
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.
30
Aromatic Hydrocarbons characteristics
lipophilic, flammable....formation of peroxides not a problem
31
Aromatic Hydrocarbons possible interactions
Ion induce dipole
32
Aromatic Hydrocarbons shelf stability
stable, won't undergo aromatic hydroxylation
33
Aromatic Hydrocarbons in vivo metabolism
aromatic hydroxylation
34
Aromatic Hydrocarbons (Aromatic Hydroxylation)
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
35
Aromatic Hydrocarbons ( what conjugate reaction aromatic-OH undergo)
Sulfation or glucuronidation becomes more water soluble
36
Enzyme involved in glucuronidation
UDP - glucuronyltransferase
37
Cofactor involved in glucuronidation
UDPGA, Uridine - 5’-diphospho-a-d--glucuronic acid
38
Enzyme involved in sulfation
sulfotransferases
39
Cofactor involved in sulfation
PAPS (3’-phosphoadenosine-5’phosphosulfate)
40
Aromatic Hydrocarbons (how to make aromatic-OH more non-polar)
It can undergo methylation Enzyme: Family of O,N,S- methyltransferases Cofactor:S-adenosyl-L-methionine (SAM)
41
Halogenated hydrocarbons characteristics
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
42
Binding possible between alcohol groups and target binding site
Strong H-bonding, utilization of intermolecular and intramolecular forces
43
Characteristics of Alcohol groups
cause hydrophilicity readily metabolized in body
44
Primary alcohol oxidized into
aldehydes and then acids
45
Secondary alcohol oxidized into
Ketones
46
Enzymes involved in alcohol oxidation
Cytochrome P450 and alcohol dehydrogenase
47
Can alcohol form Phase II metabolites?
yes, glucuronide or sulfate conjugates
48
What is unique about tertiary alcohol
stable to oxidase enzymes, won't undergo oxidation Misoprostol, tertiary alcohol incorporated to prevent oxidation
49
Phenol positioning
R Ortho Meta Para
50
Is phenol acidic?
mildy acidic due to ability to lose H atom and phenol ate stabilized by resonance, weak acid
51
pKa and acidity
The higher the Ka, the lower the pKa Low pKa = strong acid
52
EDG effect on acidity
destabilize structure and decrease acidity
53
EWG effect on acidity
stabilize structure and increase acidity
54
How to make water-soluble formulation of phenol?
treat with strong base like Na or K hydroxide to produce a salt
55
If phenol treated with sodium bicarbonate?
Nothing, won't react with weak base
56
What happen if sodium phenolate (salt) treated with strong acid
reverts back to phenol
57
Phenol air stable?
no, undergo oxidation and form quinones (para or ortho only)
58
Metabolites formed from phenol oxidation
Quinones, they are highly colored
59
How to prevent oxidation of phenol?
store in amber container, or add antioxidant
60
Phenolic-OH group during in vivo metabolism becomes
oxidized or hydroxylated
61
More soluble metabolites of phenol
glucuronide Sulfate conjugate Hydroxylation, adding another OH
62
Less soluble metabolites of phenol
methyl ether
63
Physical-chemical properties of ether
low boiling point and poor water solubility
64
Ether water solubility
less water soluble than alcohol due to weak h-bonding since no OH groups
65
Interaction ether do at binding sites
Van der Waals interaction
66
Ethers polar or non polar?
slightly polar
67
What happens to ether solubility when add alkyl groups
significantly decreased
68
Are ethers stable to on the shelf conditions
relatively stable and non-reactive one exceptions, liquid ethers in contact with atmospheric oxygen form peroxides
69
How to make ether more stable?
add copper, prevent peroxide
70
Metabolism possible with ether?
Metabolic dealkylation reaction
71
Aldehyde and ketones polar or non polar?
both polar groups
72
What type of interactions can aldehyde and ketones do at binding site
H-bond
73
"Keto"
Double bond O, 2 ch3
74
"enol"
double bond CH2, OH and CH3
75
Ketone stability on shelf
relatively nonreactive
76
Aldehyde stability on shelf
rapidly oxidized to corresponding acids if not protected form atmospheric oxygen
77
What is hemi-acetal
derived from aldehyde + alcohol and acid R,H,OH,OR1......acetal is R,H,OR1,OR1
78
What is hemi-ketal
Derived form ketone + alcohol and acid R,R1,OH,OR1.....ketal is R,R,OR1,OR1
79
Glucuronic acid is a...
hemi-acetal
80
Metabolism of aldehyde in body?
readily oxidized to form Carboxylic acids enzymes involved: Xanthine oxidase, aldehyde oxidase, and NAD-specific aldehyde dehydrogenase
81
Can aldehyde reduce in body?
Yes, via minor metabolic reaction to alcohol....become more soluble
82
Can keto reduce in body?
yes, to secondary alcohol....becomes more soluble
83
what happens when a,b-unsaturated group reduced in body
secondary alcohol is formed this reaction is often stereoselective and one isomer is formed
84
Role of amine in drug molecule
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
Does amine act as HBD or HBA
primary and secondary = HBD + HBA | tertiary = HBA
86
amines Hydrogen bond strength vs -OH group
Weaker H-bond than alcohol
87
trend of solubility for amines
1>2>3
88
EDG effect on basicity amines
Increase basicity
89
EWG effect on basicity amines
Decrease basicity
90
Basicity trend of amines
2>3>1 when ethyl group (2 CH2CH3) | 2>1>3 when methyl group
91
Methylation reaction
Phase II Enzymes: O,N,S-methyltransferases Cofactor: S-adenosyl-L-methionine (SAM) Decrease water solubility, not very common
92
Acetylation reaction
Phase II Enzymes: N-acetyltransferases Cofactors: Acetyl CoA Decrease water solubility Fast Acetylators: clear certain drugs faster Slow Acetylators: clear certain drugs slower
93
Sulfation reaction
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
Glucuronidation reaction
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
FMO
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
CYP450 info
``` 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
nitro group info
Considered polar, charged converted into amino group in body Hydroxylamine is toxic intermediate
98
Thioethers info
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
Sulfonamides info
acidic in nature weak acid, carboxamides are neutral aryl sulfonamides poor water solubility salt formation improve water solubility
100
Sulfonic acid info
more acidic than carboxylic acids due to sulfonate very water soluble due to strong dipole-ion interactions
101
Amide info
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
Enzyme involved in biotransformation of ethanol to acetic acid?
Acetaldehyde Dehydrogenase Disulfiram inhibits it
103
Esters and Lactones info
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
Carboxylic acid info
as Alkyl groups increase, solubility decrease greater H bonding than alcohol or phenols Good shelf stability
105
Enzyme involved in biotransformation of ethanol to acetic acid?
Acetaldehyde Dehydrogenase Disulfiram inhibits it
106
Mevalonic acid
key intermediate in biosynthesis of cholesterol
107
Linoleic acid
essential for synthesis of cell membranes
108
Arachidonic acid
key intermediate in synthesis of prostaglandins, prostacyclin and thromboxane
109
What to do if position on aromatic ring undergoing hydroxylation and making inactive?
replace with biosphere lie fluorine
110
Quaternary ammonium salt info
lipophilic, water soluble and stable on shelf
111
EDG effect on basicity of aromatic amines
increase basicity in meta or para position
112
EWG effect on basicity of aromatic amines
decrease basicity in meta or para position
113
predictable site of aromatic amine?
para
114
how to make aromatic amine more water-soluble
adding an acid to make salt
115
can 3 amine undergo conjugation (Phase II)?
no, due to hindrance
116
what metabolism convert amine group to non-polar group
Methylation
117
requirement for deamination of 1 amine?
carbon attached to N must have at least 1 H
118
1 amine deamination
cofactor: pyridoxal-5-phosphate to form pyridoxine enzyme: MAO and DAO
119
Metabolism of amines
``` 2/3 = dealkylation 1 = deamination ``` 2/1 can undergo conjugation (Phase II)

Pharmacology and Medical Chemistry I (30 decks)

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