Bioreductive Agents Flashcards
What are bioreductive agents? What are the used to treat?
prodrugs that are activated in vivo by reducing agents/reductase enzyme
are used to treat hypoxic cells associated with solid tumours
Why do hypoxic cells occurs? Why are they difficult to eradicate?
hypoxic cells are associated with solid tumours
- due to their rapid cell division which results in decreased oxygenation of cells
are difficult to eradicate due to
- resistant to radiotherapy because DNA damage relies on ROS
- poor delivery of therapeutics due to disrupted vasculature
What is the role of HIF in hypoxia?
HIF
- hypoxia inducible factors are transcription regulators
HIFs contain an oxygen sensitive HIF-alpha subunit
- are hydroxylated in the presence of oxygen
- leads to HIF-alpha ubiquitination and degradation
during hypoxia when oxygen levels are low, HIF is overexpressed
- enables survival of hypoxic cells by coordinating adaptive responses
= switches cell metabolism into increased glucose consumption, pyruvate, lactate and hydrogen ion production
What are the types of bioreductive drugs? How do they work?
bioreductive quinone prodrugs contain quinone moieties that are oxidising
- oxidising quinone moiety undergoes single electron reduction (SET) forming semi-quinone
- semi-quinone has a benzylic leaving group and forms quinine methide
- quinone methide is highly reactive towards nucleophiles
= can alkylate DNA
Why are bioreductive drugs specific to hypoxic cells?
bioreductive drugs have an oxidising moiety that activates the drug via capture of an electron from a reductase enzyme
- quinone
reductase enzymes are over expressed in hypoxic conditions
- NADPH-cytochrome c reductase
occurs via one electron reduction (SET)
- is reversible
- occurs under hypoxic conditions
What effect does superoxide have on bioreductive drugs? How is it produced and why?
superoxides reverses the reduction of the bioreductive drug
- reproduces the inactive prodrug
is produced by enzyme NADPH oxidase
- for use in oxygen dependent killing mechanisms of invading pathogens
What is the purpose of superoxide dismutase?
superoxide dismutase (SOD)
- converts toxic superoxide into less toxic hydrogen peroxide and oxygen
hydrogen peroxide is converted to water by proteins catalase and glutathione peroxidase
What is the difference between one and two electron reductase activation of quinone prodrugs?
one electron reductase activation
- forms semi-quinone radical anion that crosslinks DNA at C1 or C10
- forms quinone methide which is highly nucleophilic towards DNA enabling alkylation
- reduction is reversible by oxygen (forms superoxide as a result)
two electron reductase activation
- forms hydroquinone
- then forms quinone methide which is highly nucleophilic towards DNA enabling alkylation
- reduction is not reversible
How does mitomycin C (MMC) work?
MMC is reductively activated
- via 1 or 2 electron reduction
reductively activated MMC reacts with the N2 position f guanine in the minor groove of DNA
- N2 is reacted as it is more exposed than the more nucleophilic N7
form interstrand crosslinks
What is the function of NAD(P)H quinone oxidoreductase (NQO1)?
also known as DT-diaphorase
- detoxification by removal of quinones nitro, azo and iminoquinone compounds
- bioreductive activation of anti-tumour quinone prodrugs
carries out obligatory 2 electron reduction
- activates MMC
What is the ping pong mechanism of NAD(P)H quinone oxidoreductae 1 (NQO1)?
hydride transfer from NADPH to the FAD cofactor
- FAD is reduced and forms reactive FADH2
= FAD is held such that its isoalloxazine ring forms the floor of the active site cavity
release of NADP+ and hydride transfer to the substrate from the reduced cofactor (FADH2)
- reduces the quinone to form cytotoxic hydroquinone
- reforms FAD, expels NADP+
= NADPH and the substrate (quinone) never occupy the active site at the same time
