CHEM4: Antiprotozoan Bioreductive Nitroimidazoles

Question 1

What are nitroimidazoles?

Answer 1

Bioreductive prodrugs

Cytotoxic to anaerobic microorganisms + hypoxic eukaryotic cells

Question 2

What is a REDOX reaction?

Answer 2

Coupled reaction that occur when a transfer of electrons takes place

Oxidation = loss of electrons

Reduction = gain of electrons

Question 3

Most biochemical transformations = redox reactions.

Give examples.

Answer 3

• Cellular respiration
  
  • In cellular respiration, glucose = oxidised to carbon dioxide
  • Molecular oxygen = ultimate electron acceptor
  • C6H12O6 + 6 O2 → 6 CO2 + 6 H2O + energy
• Drug metabolism
• Photosynthesis
  
  • ​Carbon dioxide = reduced to sugars
  • water = electron donor
  • 6 CO2 + 6 H2O + energy → C6H12O6 + 6 O2

Question 4

What mediates biological redox reactions?

Answer 4

Redox enzymes (oxidoreductase)

These enzymes use coenzymes (NAD + NADP) as electron carriers

Most redox reactions = stereoselective because the reactants are bound by enzymes in predetermined + fixed spatial relationships

Question 5

What is an oxidation state?

Answer 5

An indicator of the degree of oxidation of an atom in a chemical compound

Also the hypothetical charge that an atom would have if all bonds to atoms of different elemts were 100% ionic

• Increase in OS = oxidation
• Decrease in OS = reduction

Question 6

What is the OS of a free element (uncombined)?

Answer 6

0

Question 7

What is the OS of a simple (monoatomic ) ion?

Answer 7

OS = equal to the net charge on the ion

Question 8

What is the OS of hydrogen _ oxygen>

Answer 8

hydrogen = 1

oxygen = -2

Question 9

The algebraic sum of oxidation states of all atoms in a neutral molecule must be _____, while in ions the algebraic sum of the oxidation states of the constituent atoms must _____

Answer 9

§The algebraic sum of oxidation states of all atoms in a neutral molecule must be zero, while in ions the algebraic sum of the oxidation states of the constituent atoms must be equal to the charge on the ion.

Question 10

The _____ the oxidation state of a given atom the _____ its degree of oxidation; the _____ the oxidation state the _____ its degree of reduction.

Answer 10

The higher the oxidation state of a given atom the greater its degree of oxidation; the lower the oxidation state the greater its degree of reduction.

Question 11

Provide examples of how to calculate OS

Answer 11

Burning hydrogen in air

• oxidation of hydrogen to water

Tollen’s test for the presence of aldehydes

• oxidation of aldehyde to carboxylic acid with silver ions

Question 12

What are ferredoxins?

Answer 12

Iron (fer-) containing redox (-redox) active proteins

Participate in redox reactions, it is an inorganic source + sink of electrons

Contain iron-sulfur clusters which are redox-active

Iron-sulfur clusters are found in ancient + conserved proteins + ancient minerals

Question 13

Describe the cellular actions of nitroimidazoles

Answer 13

Under anaerobic conditions (as they occur in protozoans and some bacteria):

• Nitroimidazoles (R-NO2) diffuse into cells and are reduced to nitro radical anions.
• In protozoans (and bacteria) nitroimidazoles are reduced by ferredoxin, whose oxidation is coupled to pyruvate-ferredoxin oxidoreductase (PFOR).
• Further reduction leads to the nitrosoimidazoles. Nitro radical anions and nitroso compounds are highly reactive and cause oxidative damage to DNA (genotoxicity, mutation) and other cellular components, leading to cell death

Under aerobic conditions (as they occur in mammalian host cells):

• O₂, the best cellular electron acceptor, oxidises the nitro radical anions back to the nitro form.
• In this process, O₂ is reduced to superoxide, which is scavenged by superoxide dismutase (SOD). This is called futile cycling. Depending on [O₂], cell death is reduced or avoided.

Question 14

Every redox reaction consist of 2 half reactions.

What are these half reactions expressed as?

Answer 14

Reductions

Each half reaction has a reduction potential E⁰

E⁰ = how easy a substance loses electrons

Question 15

How do we determine if a redox reaction will occur?

Answer 15

We compare E⁰ values of the half reactions

• the component with the more –ve E⁰ will donate electrons;
• the component with the more +ve E⁰ will accept electrons;
• the more negative E⁰ for a half-reaction, the further the equilibrium position lies to the left.
• E⁰ net is the sum of the E⁰ values of the half reactions (invert sign if half reaction occurs in opposite direction) and can be used to assess how (un)favourable a redox reaction is. If E0net > 0, reaction is spontaneous.

Question 16

Biological reduction of nitroimidazoles

Answer 16

Question 17

Describe radiotherapy + how it needs oxygen for its function?

Answer 17

Question 18

How can nitroimidazoles be used as radiosensitisers?

Answer 18