Exam 1 - Lecture 5 - 9, Organic functional groups and drug metabolism Flashcards
Lipinski’s Rule of Five
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
rank Intramolecular forces between drug and binding site
Covalent (strongest, 200 - 400kJ) irreversible
Electrostatic or Ionic ( 20 - 40 kJ)
Hydrogen bonds ( 16 - 30 kJ)
Van Der Waals (2 - 4 kJ)
Characteristics of Electrostatic or ionic bond
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
Characteristics of Hydrogen Bonds
Between deficient hydrogen and electron rich heteroatom (N or O)
optimum orientation where angle between X,H and Y is 180
H-Bond donor
Group with electron deficient hydrogen
H-Bond acceptor
Group with electron rich heteroatom
Strong hydrogen bond acceptors
carboxylate ion, phosphate ion, tertiary amine
Moderate hydrogen bond acceptors
Carboxylic acid, amide oxygen, ketone, ester, ether, alcohol
Poor hydrogen bond acceptors
Sulfur, fluorine, chlorine, aromatic ring, amide nitrogen,, aromatic amine
Good Hydrogen bond donor
Quaternary ammonium ion
Characteristics of Van Der Waals interaction
occur between hydrophobic region of drug and target
interactions drop off rapidly with distance, crucial contribution to binding
Functional groups that exhibit Van Der Waals
Alkanes
Aromatic Hydrocarbons
Halogenated Hydrocarbons
Characteristics of Dipole-dipole interaction
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
Io-dipole vs Dipole-dipole
Ion-dipole stronger
Functional groups that form dipole-dipole
Ether and amines
Functional groups that form ion-dipole
Alcohols, sulfuric acids, quaternary ammonium, phenol
Bronsted-Lowery Acid
substance capable of giving a proton, acid turned into conjugate base
Bronsted-Lowery Base
substance capable of accepting proton, base turned into conjugate acid
Bronsted-Lowery neutral
functional groups that cannot give up or accept a proton
Hydrophobic and lipophilic
Water hating and lipid loving
Hydrophilic and lipophobic
Water loving and lipid hating
Lipophilic functional groups
Aromatic hydrocarbons, Halogenated Hydrocarbons, Thioethers, Alkanes, Alkenes
Hydrophilic functional groups
Alcohols, carboxylic acids, amines
Characteristics of alkane functional groups
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
Metabolism of Alkane
Relatively nonreactive, excreted from body unchanged
Exception is oxidation of w-1 carbon by CYP450 (adding of OH)
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
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
Metabolism of Alkene
Hydration, epoxidation, peroxidation and reduction
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.
Aromatic Hydrocarbons characteristics
lipophilic, flammable….formation of peroxides not a problem
Aromatic Hydrocarbons possible interactions
Ion induce dipole
Aromatic Hydrocarbons shelf stability
stable, won’t undergo aromatic hydroxylation
Aromatic Hydrocarbons in vivo metabolism
aromatic hydroxylation
Aromatic Hydrocarbons (Aromatic Hydroxylation)
- involves initial epoxidation
- Intermediate epoxides toxic, responsible for carcinogenic effect
- Mediated by several CYP450 isoforms
- Phase I reaction, significantly improves solubility
Para position preferred, least hindered and easiest to attack
Aromatic Hydrocarbons ( what conjugate reaction aromatic-OH undergo)
Sulfation or glucuronidation
becomes more water soluble
Enzyme involved in glucuronidation
UDP - glucuronyltransferase
Cofactor involved in glucuronidation
UDPGA, Uridine - 5’-diphospho-a-d–glucuronic acid
Enzyme involved in sulfation
sulfotransferases
Cofactor involved in sulfation
PAPS (3’-phosphoadenosine-5’phosphosulfate)
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)
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
Binding possible between alcohol groups and target binding site
Strong H-bonding, utilization of intermolecular and intramolecular forces
Characteristics of Alcohol groups
cause hydrophilicity
readily metabolized in body
Primary alcohol oxidized into
aldehydes and then acids
Secondary alcohol oxidized into
Ketones
Enzymes involved in alcohol oxidation
Cytochrome P450 and alcohol dehydrogenase
Can alcohol form Phase II metabolites?
yes, glucuronide or sulfate conjugates
What is unique about tertiary alcohol
stable to oxidase enzymes, won’t undergo oxidation
Misoprostol, tertiary alcohol incorporated to prevent oxidation
Phenol positioning
R
Ortho
Meta
Para
Is phenol acidic?
mildy acidic due to ability to lose H atom and phenol ate stabilized by resonance, weak acid
pKa and acidity
The higher the Ka, the lower the pKa
Low pKa = strong acid
EDG effect on acidity
destabilize structure and decrease acidity
EWG effect on acidity
stabilize structure and increase acidity
How to make water-soluble formulation of phenol?
treat with strong base like Na or K hydroxide to produce a salt
If phenol treated with sodium bicarbonate?
Nothing, won’t react with weak base
What happen if sodium phenolate (salt) treated with strong acid
reverts back to phenol
Phenol air stable?
no, undergo oxidation and form quinones (para or ortho only)
Metabolites formed from phenol oxidation
Quinones, they are highly colored
How to prevent oxidation of phenol?
store in amber container, or add antioxidant
Phenolic-OH group during in vivo metabolism becomes
oxidized or hydroxylated
More soluble metabolites of phenol
glucuronide
Sulfate conjugate
Hydroxylation, adding another OH
Less soluble metabolites of phenol
methyl ether
Physical-chemical properties of ether
low boiling point and poor water solubility
Ether water solubility
less water soluble than alcohol due to weak h-bonding since no OH groups
Interaction ether do at binding sites
Van der Waals interaction
Ethers polar or non polar?
slightly polar
What happens to ether solubility when add alkyl groups
significantly decreased
Are ethers stable to on the shelf conditions
relatively stable and non-reactive
one exceptions, liquid ethers in contact with atmospheric oxygen form peroxides
How to make ether more stable?
add copper, prevent peroxide
Metabolism possible with ether?
Metabolic dealkylation reaction
Aldehyde and ketones polar or non polar?
both polar groups
What type of interactions can aldehyde and ketones do at binding site
H-bond
“Keto”
Double bond O, 2 ch3
“enol”
double bond CH2, OH and CH3
Ketone stability on shelf
relatively nonreactive
Aldehyde stability on shelf
rapidly oxidized to corresponding acids if not protected form atmospheric oxygen
What is hemi-acetal
derived from aldehyde + alcohol and acid
R,H,OH,OR1……acetal is R,H,OR1,OR1
What is hemi-ketal
Derived form ketone + alcohol and acid
R,R1,OH,OR1…..ketal is R,R,OR1,OR1
Glucuronic acid is a…
hemi-acetal
Metabolism of aldehyde in body?
readily oxidized to form Carboxylic acids
enzymes involved: Xanthine oxidase, aldehyde oxidase, and NAD-specific aldehyde dehydrogenase
Can aldehyde reduce in body?
Yes, via minor metabolic reaction to alcohol….become more soluble
Can keto reduce in body?
yes, to secondary alcohol….becomes more soluble
what happens when a,b-unsaturated group reduced in body
secondary alcohol is formed
this reaction is often stereoselective and one isomer is formed
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
Does amine act as HBD or HBA
primary and secondary = HBD + HBA
tertiary = HBA
amines Hydrogen bond strength vs -OH group
Weaker H-bond than alcohol
trend of solubility for amines
1>2>3
EDG effect on basicity amines
Increase basicity
EWG effect on basicity amines
Decrease basicity
Basicity trend of amines
2>3>1 when ethyl group (2 CH2CH3)
2>1>3 when methyl group
Methylation reaction
Phase II
Enzymes: O,N,S-methyltransferases
Cofactor: S-adenosyl-L-methionine (SAM)
Decrease water solubility, not very common
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
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
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
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)
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
nitro group info
Considered polar, charged
converted into amino group in body
Hydroxylamine is toxic intermediate
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)
Sulfonamides info
acidic in nature
weak acid, carboxamides are neutral
aryl sulfonamides poor water solubility
salt formation improve water solubility
Sulfonic acid info
more acidic than carboxylic acids due to sulfonate
very water soluble due to strong dipole-ion interactions
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
Enzyme involved in biotransformation of ethanol to acetic acid?
Acetaldehyde Dehydrogenase
Disulfiram inhibits it
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
Carboxylic acid info
as Alkyl groups increase, solubility decrease
greater H bonding than alcohol or phenols
Good shelf stability
Enzyme involved in biotransformation of ethanol to acetic acid?
Acetaldehyde Dehydrogenase
Disulfiram inhibits it
Mevalonic acid
key intermediate in biosynthesis of cholesterol
Linoleic acid
essential for synthesis of cell membranes
Arachidonic acid
key intermediate in synthesis of prostaglandins, prostacyclin and thromboxane
What to do if position on aromatic ring undergoing hydroxylation and making inactive?
replace with biosphere lie fluorine
Quaternary ammonium salt info
lipophilic, water soluble and stable on shelf
EDG effect on basicity of aromatic amines
increase basicity in meta or para position
EWG effect on basicity of aromatic amines
decrease basicity in meta or para position
predictable site of aromatic amine?
para
how to make aromatic amine more water-soluble
adding an acid to make salt
can 3 amine undergo conjugation (Phase II)?
no, due to hindrance
what metabolism convert amine group to non-polar group
Methylation
requirement for deamination of 1 amine?
carbon attached to N must have at least 1 H
1 amine deamination
cofactor: pyridoxal-5-phosphate to form pyridoxine
enzyme: MAO and DAO
Metabolism of amines
2/3 = dealkylation 1 = deamination
2/1 can undergo conjugation (Phase II)
