W8 Anticancer drugs l (SF) Flashcards
Cytotoxic or chemotherapeutic drugs
Most traditional anticancer drugs working by disrupting the function of DNA.. How? (3)
1) Act on DNA directly
2) Act indirectly: inhibition enzymes involved in the synthesis of of DNA itself
or of nucleotide building blocks
3) Act on microtubule dynamics involved in mitosis
What are the 3 main classes
of cytotoxic drugs?
1-Drugs targeting DNA structure & template activity
2-Antimetabolites: target enzymes involved in the synthesis of DNA itself or
of nucleotide building blocks
3-Mitotic arrest agents target microtubules
Sites of actions of cytotoxic drugs:
Cytotoxic drugs effects related to the cell cycle
Active at specific points in the cell cycle
* Antimetabolites: S phase
(synthesis of nucleosides)
* Intercalators and topoisomerases:
end of G1, during S and early G2
(DNA strands are being used for
synthesis of DNA)
* Mitotic inhibitors: M phase- vinca
early -taxoids late
* Alkylating agents: attack DNA,
single or double stranded throughout the whole cell cycle
DNA Alkylating and Crosslinking Agents:
What are the features?
o Highly electrophilic compounds: react with nucleophilic groups on DNA (mainly the N-7 position of deoxyguanylates) → strong covalent bonds
* 2 alkylating groups → covalent cross-linking of adjacent strands of DNA
(inter-strand cross-linking) → disrupted replication/transcription → cell tries
unsuccessfully to repair → cell cycle arrest → apoptosis
o Organoplatinum: binding to adjacent guanine nucleotides on a single strand of
DNA → intra-strand DNA cross-linking
o Higher effect in tumour cells: divide more rapidly (high DNA synthesis)
o All phases of the cell cycle are susceptible (not cell cycle specific) but they are more toxic in late G1 or S phases (DNA is unwinding and exposing nucleotides)
Issues with DNA Alkylating and Crosslinking Agents? (3)
o Most alkylating agents require chemical or enzymatic activation
o Poor selectivity: react with nucleophilic groups on proteins as well
o Can damage DNA of healthy cells: intrinsically mutagenic and carcinogenic!
Five main groups that form DNA Alkylating and Crosslinking Agents? (for info?) he skipped
- Nitrogen Mustards
- Nitrosoureas
- DNA methylators
- Organoplatinum complexes (metallating agent)
- Miscellaneous DNA alkylators
All frequently include in combination therapy
DNA Alkylating and Crosslinking Agents:
Effects of alkylating agents on DNA
- Crosslinked guanine bases =DNA replication impaired
- Guanine N7 alkylation can give an enol
tautomer which can bind to thymidine = Mismatching of bases- leading to defective coding of proteins - Guanine N7 alkylation can cause cleavage of imidazole ring = Excision of guanine residue leading to DNA breakage
DNA Alkylating and Crosslinking Agents
1. Nitrogen Mustards
Structure:
R= can be either aliphatic or aromatic; prime determinant of chemical reactivity, oral bioavailability, nature/extent of adverse effects
Chlorine atoms: decrease N basic strength through a strong negative inductive effect → unionised drug predominates at physiologic pH → lone pair of electrons on N allows for the formation of the highly electrophilic aziridinium ion, which is
the reactive DNA-destroying intermediate
e.g. Chlormethine Chlorambucil Cyclophosphamide
Nitrogen Mustards: MoA
- Intramolecular nucleophilic displacement
- Highly electrophilic azirdinium ion
- Mono-alkylation
- Repeat for the second Cl
Aziridinium ion (reactive 𝝱-carbon)
-strained three membered ring
-strong negative inductive effect of the cationic nitrogen
Mono-alkylated
lone pair on the mustard N is regenerated
Di-alkylation (bifunctional) (guanine N-7): cross-linking between DNA chains or within same chain → DNA strands cannot separate nor replicate, transcription of DNA to RNA is halted
DNA Alkylating and Crosslinking Agents
Nitrogen Mustards: the R group is
important
- (Chlormethine) CH3 → electrons to the amine → enhances N nucleophilicity → very reactive (tumour and healthy cells) with unpaired DNA and other cell
nucleophiles (SH, OH and NH of amino acids, and H2O body) → no tissue or cell specificity → increased risk of serious adverse effects and use-limiting toxicity Too reactive for oral route - (Chlorambucil) Phenyl → stabilise the lone pair through resonance →
significantly slows the rate of intramolecular nucleophilic
attack, aziridinium ion formation, and DNA alkylation. Reactivity sufficiently controlled to permit oral administration, attenuate the severity of adverse effects, enhanced tissue selectivity
Nitrogen Mustards: Cyclophosphamide
Is what type of drug
Chiral prodrug: requiring activation by metabolic and nonenzymatic processes
See mechanism on slide
DNA Alkylating and Crosslinking Agents
Nitrogen Mustards: Cyclophosphamide
Toxic effects?
- Most common alkylating agent in cancer chemotherapy, oral administration (or i.v.), for leukaemias, limphomas, sarcoma, solid tumours
- Metabolic activation in the liver: lowered GI toxicity and less non-specific toxicity
Toxic effects:
* CYP3A4/CYP2B6: inactivate cyclophosphamide by N-dechloroethylation → chloroacetaldehyde formed → electrophilic alkylates Cys residues of critical cell proteins→ highly nephrotoxic and neurotoxic
* Acrolein: very electrophilic/highly reactive species→ generated in liver, readily conjugates with GSH→ delivered to the bladder for excretion → extensive
damage to cells of the kidney and bladder. If low GSH → acrolein will be attacked by the SH of bladder cell Cys residues → haemorrhagic cystitis
Nitrogen Mustards: Cyclophosphamide
To minimise the risk of haemorrhagic cystitis what is given?
Mesna as adjuvant therapy
(active sylfhydryl reagent)
DNA Alkylating and Crosslinking Agents
Nitrosoureas: MoA
Chloroethyl-containing nitrosoureas (CNUs)
Decompose spontaneously in the aqueous environment of the cell → active species…
Cross-linking of N1-Guanine-N3 Cytosine
Alkylatkion with O6 guanine
Carbamoylation of Lys residues
Highly lipophilic drugs → cross BBB → treat Brain tumour
See Mechanism on slide
