Toxicophores

Question 1

Define biophore

Answer 1

Is a structural moiety that is statistically related to biological activity

Question 2

What are the most importatant nitrogen-containing toxicophores?

Answer 2

• aromatic nitro
• aromatic amine
• nitrosoamine
• aziridine
• aromatic azo
• nitrogen mustard
• hydrazine
• hydrazide

Question 3

What is the toxic mechanism of nitrogen-containing toxicophores?

Answer 3

Nitrogen has the ability to “steal/absorb” positive charges –> makes them very reactive

1. Nitrogen absorbs a positive charge from oxygen
2. Nitrogen becomes positively charged (formation of nitronium ion)
3. The positive charge can be relocated in the aromatic ring

Question 4

Which toxicophores are considered mutagenic?

Answer 4

Mutagenic compounds:
- Double-bonded azo type
- Tri-membered aziridine
- Aromatic amine
- Polycyclic system
- N-heterocyclic-quinone-redox-cycling
- Quinone
- Polycyclic aromate
- Nitroso
- Azole
- Aliphatic hallide
- Epoxide

Question 5

What is the purpose of an Ames in vitro Assay?

Answer 5

To detect genetic damage caused by chemicals.

A chemical is considered mutagenic (Ames test positive) when its addition to the assay causes a significant increase in the number of bacterial colonies compared to a control experiment

Question 6

What characterizes azoles as toxicophores?

Answer 6

The azole structure contains an sp2-hybridized nitrogen atom in the imidazole ring, which has an extremely high affinity for Fe3+ found in cytochrome-P-450 (CYP) enzymes.

This ability is applied in the therapeutic mechanism but is also the reason for toxicity.

• Therapeutic: the azole covalently binds to the fungal CYP51 –> obstructing the production of ergosterol from lanosterol –> inhibits fungal growth and function
• Toxic: binding to fungal CYP51 is not specific, and the azole may also bind to other CYP enzymes, including human CYPs –> may interfere with steroidogenesis

Question 7

Which toxicophores are considered carcinogenic?

Answer 7

Same pattern as mutagenecity (nitrogen):
* aromatic amines
* amides
* hydroxylamines
* nitrosoamines
* azo compounds

But also:
* Lactone structure (bizarre oxygen structures)
* Polyaromatic hydrocarbons

Question 8

What is the general mechanism for cancer?

Answer 8

Cancer mechanisms:
Phase 1 hydroxylation –> Radical on the carbon due to the azotype double bond.

Phase 1 epoxidation –> Creation of epoxide –> very reactive and toxic compound

Phase 2 acetylation –> Positive charge on nitrogen

Question 9

How is benzo[a]pyrene (BaP) detoxified?

Answer 9

Phase 1: CYP1A family adds an epoxide on carbon 4 and 5 to benzo(a)pyrene (BaP-4,5-oxide)

Phase 2:
1) Conjugation with glutathione by GSH-S-transferase (GST)
OR
2) addition of water followed by conjugation with UDP-glucuronic acid by UDP-glucuronosyl transferase (UGT)

Question 10

What is the toxic mechanism of benzo[a]pyrene (BaP)?

Answer 10

–> epoxidation of carbon 7,8 (BaP-7,8-oxide)
–> addition of water molecule
–> CYP1A1 will interfere and add another epoxide on carbon 9,10
–> high affinity to nitrogen in guanine
–> BaP-7,8-diol 9,19-oxide will attack guanine
–> substitution of adenine instead of cytidine
–> DNA adduct
–> Mutation, cancer

Question 11

Which substructures are detoxifiers?

Answer 11

• Sulfonamides, SO2NH
• Sulfonic acid, SO2OH
• Aryl sulfonyl
• Sulfinyl
• Fluorides (less reactive than chlorides and bromides), CF3
• COOH (not so powerful)

Question 12

What is the mechanism behind detoxifiers?

Answer 12

Detoxifiers are either:
1) strong electron-withdrawing groups and they create a large charge distribution near the toxicophore –> less focused reactions
2) groups that induce steric hindrance near the toxicophore –> makes it hard to react

Question 13

Which addition of which types of groups can lead to increased reactivity?

Answer 13

Electrophiles, free radicals, nucleophiles, redox-active reagents