Making and breaking covalent bonds

Question 1

What are the properties of covalent bonds in terms of making and breaking them (7)

Answer 1

1. Too strong to be cleaved in physiological conditions
2. not frequently used/not desirable in drugs
3. Covalent bonds can be cleaved by enzymes (not always), but the most common reversal mechanism is through biomacromolecule turnover.
4. Protein synthesis
5. Nucleic acid synthesis
6. Selectivity is a BIG concern!
7. Duration of action is a concern.

Question 2

What are alkylation reactions

Answer 2

When a nucleophile (EDG) attacks an electron-poor carbon on an alkyl chain.

Question 3

What are examples of nucleophiles (EDGs) (6)

Answer 3

Question 4

What are acylation reactions

Answer 4

When a nucleophile (EDG) attacks an acyl group (R-C=O)

Question 5

What are the advantages of covalent bond formation (4)

Answer 5

1. Alkylating anticancer (chlorambucil)
2. Cycloxygenase inhibitors (aspirin)
3. Antithrombotic agents (thienopirine)
4. β-lactams (cefotixin)

Question 6

What are the disadvantages of covalent bond formation (2)

Answer 6

1. Nucleophilic functions are ubiquitous on biomacromolecules
2. An electrophilic xenobiotic or drug metabolite can cause toxicity

Question 7

What are prodrugs

Answer 7

When known enzymatic activity can be exploited to transform an inactive molecule into a drug

Question 8

What is important to know with prodrugs (9)

Answer 8

1. Know the enzyme (where it can be found in the body, what group is a favourite substrate…)
2. Know the chemistry of the prodrug
3. Absorption and Distribution - to increase lipid solubility to penetrate membranes for better absorption
4. Instability - to prevent rapid metabolism; avoid first-pass effect
5. Site Specificity - to target a particular organ or tissue if a high concentration of certain enzymes is at a particular site or append something that directs the drug to a particular site (often tried to limit the toxic side effect of anticancer drugs).
6. Prolonged Release - to attain a slow, steady release of the drug
7. Toxicity – to make less toxic until it reaches the site of action
8. Poor Patient Acceptability – to remove an unpleasant taste or improve compliance
9. Formulation Problems – to convert a drug that is a gas or volatile liquid into a solid

Question 9

What groups can we mask (4)

Answer 9

1. Alcohols/phenols
2. Carboxylic acids
3. Amines
4. Aldehydes

Question 10

How are alcohols/phenols and carboxylic acids masked

Answer 10

Question 11

How are amides masked

Answer 11