Midterm Extras

Question 1

Omeprazole

Answer 1

• Prodrug that rearranges into an active achiral drug; protonated at the most basic N in the stomach via covalent modification (do not protonate at NH bc breaks aromaticity)
• Aromatic at beginning then intramolecular rxn makes it non-aromatic, but reestablished in active compound
• N attacks S (bonded to O) (kicks off OH) and reestablish aromaticity
• Activates sulfur as electrophile, making active molecule

Question 2

Omeprazole -> Patent

Answer 2

Prodrug is chiral, active species is chiral
- Omeprazole has 2 enantiomers (other is esomeprazole)

• When omeprazole (racemic mixture) lost patent protection, the drug company decided to use the S enantiomer that was optically pure (more potent) aka less side effects; changed name to esomeprazole
• Single enantiomer crucial in drug development
• Achiral version plays role in specific recognition of drug and potentially less side effects

Question 3

Covalent Functionality

Answer 3

Typically the reactive part / electrophile is an unsaturated ketone or epoxide

Question 4

Mustard Gas

Answer 4

Intramolecular SN2 Reaction
- Nitrogen forms epoxide with itself so that the nucleophile can attack it, kicks Cl off by alkylation and breaks ring first then reforms it

• N attacks C (kicks off Cl), forms epoxide, Nuc attacks epoxide, N attacks C (kicks off Cl again), Nuc attacks epoxide again, reforms ring

Question 5

Aspirin

Answer 5

Acetylsalicylic acid inactivates COX enzyme, also acts as a covalent modifier, but has a reversible binding element to it
- Cox attaches to acetylsalicylic acid by breaking apart the ester region; cox region then gets cleaved off and is inactive -> blocks sensation of pain

Question 6

Disulfram

Answer 6

• Covalent drug, disulfide region is reactive
• Disulfram targets acetaldehyde dehydrogenase
• Our body hates aldehydes so tries to covert it to AA through AD (but makes us feel hangover).
• Disulfram works by blocking the breakdown of alcohol in the body so that we do not feel negative effects -> used to treat chronic alcoholism

Where does disulfram inhibit acetaldehyde dehydrogenase? -> Attacks S-S bond in disulfram to form new S-S bond in acetaldehyde dehydrogenase, which makes it inactive

Question 7

Ibrutnib

Answer 7

BTK Inhibitor

• Covalent adducts warhead close to reactor
• Reacts with an amino acid on enzyme
• Has a recognition of kinase element to bind to which acts as an inhibitor (reversible) then a covalent bond is formed (irreversible)
• Recognition element and reactive group = good selectivity of drug
• Warhead: the double bond next to the carbonyl
• Recognition: position warhead next cysteine so it can form a covalent bond