Prodrugs and Their Mechanisms

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Questions and Answers

What is estramustine classified as due to its properties?

A bioprecursor prodrug.

A carrier-linked prodrug.

An inactive compound.

A mutual prodrug. (correct)

What is an effect of 17α-estradiol on prostate cancer cells?

It has no effect on cancer cells.

It slows the growth of cancer cells. (correct)

It promotes the growth of cancer cells.

It increases testosterone levels.

How can the water solubility of estradiol be increased?

Through phosphorylation. (correct)

By oxidation of its functional groups.

By reducing its molecular size.

By adding more carbon chains.

What is a major drawback of bioprecursor prodrugs?

They may undergo alternate metabolic pathways that inactivate the compound. Signup and view all the answers

How does sulindac, as a prodrug, affect GI irritation?

It reduces GI irritation by being administered in inactive form. Signup and view all the answers

What happens to sulindac after absorption in the small intestine?

It is converted to an inactive sulfone. Signup and view all the answers

What characteristic of hetacillin enhances its lipophilicity?

Reactivity with acetone leading to an imidazolidinone ring. Signup and view all the answers

What happens to the amide nitrogen and alpha-amino functionalities in hetacillin?

They react with acetone to form an imidazolidinone. Signup and view all the answers

What is the primary advantage of converting drugs containing carboxylic acid or alcohol functionalities to esters?

Esters can be hydrolyzed to yield active drugs. Signup and view all the answers

Which type of enzymes are primarily responsible for hydrolyzing ester prodrugs?

Esterases Signup and view all the answers

What characteristic of the promoiety, such as acetone, is essential for its use as a prodrug?

It must be nontoxic and easily removable. Signup and view all the answers

Which factor is NOT mentioned as a benefit of decreasing the hydrophilicity of a prodrug?

Enhanced effectiveness against infection Signup and view all the answers

Which of the following accurately describes a reason for the popularity of esters as prodrugs?

They can be formed from drugs with alcohol or carboxylic acid functionalities. Signup and view all the answers

What is the role of microflora present within the gut in relation to prodrugs?

They can hydrolyze esters. Signup and view all the answers

When manipulating the electronic properties of the pro-moiety, what is one outcome that can be controlled?

The rate and extent of hydrolysis Signup and view all the answers

Which of these statements about esters as prodrugs is FALSE?

Esters are typically more soluble than their parent drugs. Signup and view all the answers

What happens to the azo linkage in sulfasalazine within the gut?

It is broken down by azo reductases. Signup and view all the answers

What is the primary active agent released from sulfasalazine?

Aminosalicylic acid Signup and view all the answers

How does the prodrug approach benefit the treatment of ulcerative colitis?

It prevents systemic absorption of the active agent. Signup and view all the answers

What type of compound is methenamine classified as?

Prodrug Signup and view all the answers

What occurs during the activation of bioprecursor prodrugs?

They are converted to active drug through metabolic or chemical transformation. Signup and view all the answers

What is the main function of the quinone functionality in mitomycin C?

To undergo reduction to hydroquinone Signup and view all the answers

Which type of activation is most commonly seen in bioprecursor prodrugs?

Oxidation Signup and view all the answers

Which property of mitomycin C makes it less selective for hypoxic cells?

The high reduction potential of its quinone Signup and view all the answers

What is the role of enteric-coated capsules in the delivery of methenamine?

They protect the drug from premature hydrolysis in the stomach. Signup and view all the answers

What is a consequence of the acidic pH in the urine for methenamine?

It catalyzes the chemical hydrolysis to yield formaldehyde. Signup and view all the answers

What is the primary mechanism by which tirapazamine activates in hypoxic conditions?

Reduction by cytochrome P-450 enzymes Signup and view all the answers

How does the hydroquinone formed from mitomycin C contribute to its mechanism?

It participates in expulsion of methoxide and loss of carbamate Signup and view all the answers

What characteristic makes tirapazamine a more selective agent than mitomycin C?

Its selectivity for hypoxic cells being 100 to 200 times greater Signup and view all the answers

What type of radical species is generated during the activation of tirapazamine?

Carbon-centered radical Signup and view all the answers

What is one notable difference between the activation of mitomycin C and tirapazamine?

Mitomycin C requires reduction of a quinone functionality Signup and view all the answers

What happens to the DNA under aerobic conditions when mitomycin C is activated?

Hydroxyl radicals are produced, causing chain breaks Signup and view all the answers

What is the primary purpose of phosphorylation in metabolic functions?

To produce high-energy phosphodiester bonds Signup and view all the answers

How does phosphorylation affect antiviral agents like nucleosides?

It activates them by converting them to nucleotides Signup and view all the answers

Which of the following describes the selective toxicity of nucleoside antiviral agents?

They are preferentially phosphorylated in infected cells Signup and view all the answers

What is the role of idoxuridine as an antiviral agent?

To be phosphorylated by viral thymidine kinase Signup and view all the answers

What is a consequence of incorporating phosphorylated antiviral agents into DNA?

It disrupts DNA's function as a template Signup and view all the answers

Which factor contributes to the selectivity of antiviral agents over normal cells?

Preference of the drug for viral enzymes Signup and view all the answers

What is the likely effect of using prodrug approaches in antiviral therapy?

Increased cell penetration of the active drug Signup and view all the answers

What can be inferred about the potential toxicity of idoxuridine?

It poses significant toxicity to normal cells Signup and view all the answers

Study Notes

Estramustine

Estramustine is a mutual prodrug, combining both steroid (17-estradiol) and mustard activity.
17-estradiol has an antiandrogenic effect on the prostate, slowing prostate cancer cell growth.
Phosphorylation of estradiol increases its water solubility, making it a prodrug modification.
Both carbamate and phosphate esters in estramustine are hydrolyzed by chemical or enzymatic means.

Bioprecursor Prodrugs

Bioprecursor prodrugs rely on metabolism to activate them, unlike carrier-linked prodrugs.
Sulindac is an example of a bioprecursor prodrug:
- It's inactive as the sulfoxide but needs to be reduced metabolically to the active sulfide.
- Administration of the inactive form reduces gastrointestinal irritation associated with the sulfide.
- Sulindac is absorbed in the small intestine, reduced to the active sulfide, and may be inactivated by oxidation to sulfone.

Chemical Activation of Prodrugs

Some prodrugs rely on chemical mechanisms for conversion to their active form.
Hetacillin is a prodrug of ampicillin, modified with acetone to form an imidazolidinone ring.
The acetone modification decreases the basicity of the -amino group, making it more lipophilic for absorption.
Chemical hydrolysis regenerates ampicillin after absorption, releasing the active drug.

Prodrugs of Carboxylic Acids and Alcohols

Prodrugs containing carboxylic acid or alcohol functional groups can be converted to esters.
Ester hydrolysis is a common activation mechanism, catalyzed by various esterases in plasma and tissues.
Ester prodrugs benefit from their ease of formation and hydrolysis, allowing for customized lipophilicity.

Prontosil and Sulfasalazine

Prontosil is not used anymore but illustrates the azo linkage seen in sulfasalazine.
Sulfasalazine, used for ulcerative colitis, is cleaved by gut microflora azo reductases.
Cleavage releases aminosalicylic acid, a colon-specific anti-inflammatory agent, and sulfapyridine.
This approach concentrates the active agent at the site of action, minimizing systemic absorption.

Carbonyl Prodrug Derivatives

Several functionalities have been evaluated for carbonyl prodrugs (e.g., aldehydes and ketones), but have not found wide clinical use.
Methenamine is a prodrug that releases formaldehyde in urine, acting as an antibacterial.
Methenamine is administered in enteric-coated capsules to prevent premature hydrolysis in the stomach.
Formaldehyde is released in urine, acting as an antibacterial against bacterial nucleophiles.

Bioprecursor Prodrug Activation

Bioprecursor prodrugs do not contain a carrier or promoiety, but rely on metabolic or chemical transformation to the active drug.
Common activation methods include oxidative activation, reductive activation, phosphorylation, and chemical activation.

Reductive Activation of Mitomycin C

Mitomycin C, used for bladder and lung cancer, is a good example of reductive activation.
Mitomycin C contains a quinone that is reduced to a hydroquinone.
This reduction alters the electron pair of the nitrogen, allowing it to participate in alkylating DNA.
Mitomycin C's selectivity for hypoxic cells is minimal, but analogues are being explored for better selectivity.

Tirapazamine for Hypoxic Cells

Tirapazamine, undergoing phase III clinical trials, shows greater selectivity for hypoxic cells than mitomycin C.
It is activated by a one-electron reduction, catalyzed by cytochrome P-450 and reductase, forming a radical species.
The radical species initiates DNA chain breaks under hypoxic conditions.

Phosphorylation for Bioactivation

Phosphorylation is a common metabolic process, producing high-energy phosphodiester bonds like those in ATP and GTP.
Phosphorylation can activate molecules by introducing a leaving group, which can be displaced by an incoming nucleophile.
Phosphorylation is crucial for the bioactivation of antiviral agents, converting nucleosides to nucleotides.

Antiviral Prodrug Activation

Antiviral agents often disrupt DNA or RNA synthesis by being converted to triphosphates.
Selectivity for viral kinase enzymes over mammalian kinases is important for antiviral prodrugs.

Idoxuridine as an Example

Idoxuridine, a nucleoside antiviral, enters cells and is phosphorylated preferentially by viral thymidine kinase.
This preferential phosphorylation leads to greater activation in virally infected cells, providing some selective toxicity.
Activated idoxuridine inhibits DNA synthesis by blocking viral DNA polymerase and causing incorrect base pairing.
The prodrug approach enhances cell penetration and can contribute to selective toxicity.

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Description

This quiz explores the concept of prodrugs, including specific examples like Estramustine and Sulindac. Learn about their mechanisms of action, metabolism, and how these drugs are activated in the body. Test your understanding of the chemistry behind prodrugs and their clinical applications.