Alkylators and topoisomerase inhibitors W5 Flashcards
What are nitrogen mustards
are alkylating agents—they work by adding alkyl groups to DNA. This interferes with DNA replication and transcription, leading to cell death, especially in rapidly dividing cells like cancer cells.
What are nitrogen mustards derived from
Sulphur mustards
Used i WW1 as mustard gas
Sulphur mustard vs nitrogen mustard
Nitrogen showed more potential and sulphur was considered too toxic for systemic use
N-mustard has an extra methy group on the N whereas S-mustard doesnt
How to N-mustards work
They form cross-links between DNA strands, preventing the DNA from uncoiling and separating properly as they stop DNA polymerase from separating the strands
This blocks cell division and leads to apoptosis (programmed cell death).
Where is the predominant cross link
Between N7 of guanine on 2 strands = an inter strand cross link
N7
Nucleophilic and has a lone pair and full of e-
2 types of cross link
Intra-strand and inter-strand
Intra-strand
chemical bond formed between two bases on the same strand of DNA.
bends or distorts the DNA strand, preventing it from uncoiling or being read properly by enzymes during replication or transcription.
Analogy: Think of tying a knot in a single thread.
Inter-strand
chemical bond formed between two bases on opposite strands of DNA.
locks the two DNA strands together so they can’t separate, which completely blocks DNA replication and transcription.
Analogy: Like stapling two sides of a zipper together so it can’t open.
Why are these linkages important in cancer treatment
Both inter- and intra-strand crosslinks are types of DNA damage that stop cancer cells from dividing.
Inter-strand crosslinks are more toxic and harder for the cell to repair, which is why they are especially powerful in chemotherapy.
What is a SN1 reaction
Substitution nucleophilic unimolecular
Is a 2-step reaction
The leaving group if replaced by a Nu:
The rate depends on the conc of the substrate (hence unimolecular)
Steps of SN1 reaction
Step 1: Formation of the Carbocation
- The leaving group (like Cl⁻ or Br⁻) breaks off from the substrate, forming a carbocation (positively charged carbon).
- This step is slow and determines the overall reaction rate.
Step 2: Nucleophilic Attack
- A nucleophile (like H₂O, OH⁻, or NH₃) then attacks the carbocation.
- This step is fast.
Tips for spotting an SN1 reaction
- Substrate is tertiary or secondary (stable carbocation).
- Weak nucleophile (e.g., water or alcohol).
- Good leaving group (like halides, F, Cl, Br, I)
How to Tell if a Substrate is Primary, Secondary, or Tertiary
Primary = bonded to 1 other C
Secondary = bonded to 2 other C
Tertiary = bonded to 3 other C
What is a SN2 reaction
Substitution Nucleophilic Bimolecular
one-step reaction where a nucleophile replaces a leaving group.
The reaction rate depends on both the substrate and the nucleophile
How does a SN2 reaction work
The nucleophile attacks the carbon from the opposite side of the leaving group.
At the same time, the leaving group leaves.
No carbocation is formed
DNA alkylation
transfer of an alkyl group (–CH₃, –CH₂CH₃, etc.) to DNA bases, usually guanine, which leads to disruption of base pairing, DNA crosslinking, and replication errors.
Mechanism of DNA alkylation
Form electrophile
Nu attack by DNA base
Nitrogen mustards act through
two substitutions
Step 1 : Formation of the Aziridinium Ion (First Substitution)
- lone pair on N attack one of its own adjacent CH2CH2Cl arms
- forms a 3-memb ring (aziridinium)
Step 2: Attack by DNA Base (Nucleophilic Substitution)
- Nu from DNA attacks to arzidinium ion and opens the ring to forms a covalent bond
Step 3–4: Repeat with the Second Arm (Second Substitution)
- the other CH2CH2Cl arms on the N-mustard reacts in the same way as the other arm to form a 2nd Arzidinium ion
Alkyl mustard vs aniline mustard
Alkyl mustard has 2 arms of CH2CH2Cl with a N in the middle and a single CH3 off the middle N
Aniline mustard has the same 2 arms and middle N but has an aromatic ring off the N
Benefits of mustards in cancer treatment
Effective against rapidly dividing cells: Cancer cells, due to their rapid growth and division, are highly sensitive to DNA damage.
Able to treat a variety of cancers: They have broad applications in oncology, treating blood cancers (like lymphoma) and solid tumors (like breast and ovarian cancers).
Drawbacks of mustards in cancer treatment
Damage to normal cells: Nitrogen mustards also damage normal healthy cells, especially those that divide rapidly, such as Bone marrow
Gastrointestinal tract (can cause nausea, vomiting)
Hair follicles (can lead to hair loss)
Side effects: Due to the systemic nature of chemotherapy, nitrogen mustards often lead to acute side effects like nausea, fatigue, hair loss, and immunosuppression.
Carcinogenic potential: Since they are DNA alkylators, nitrogen mustards themselves can be carcinogenic over long-term use. They can potentially cause secondary cancers in some patients after treatment.
Prodrugs
Not active in the body
Activated by something in the cellular environment to release the active compound
For cancers, we try choose an environment that is different from that of healthy cells
Cyclophosphamide – nitrogen mustard prodrug
not in its active form when it is administered but becomes activated in the body.
Once activated, it functions as an alkylating agent to damage DNA in cancer cells and induce cell death.
a phosphoramide mustard, meaning it contains a phosphorus group
Once inside the body, cyclophosphamide undergoes metabolic activation in the liver through the action of cytochrome P450 enzymes.
Once activated it alkylates DNA, primarily at the N7 position of guanine.
