Lec 17- alkylating agents Flashcards
1
Q
Alkylating agents
A
- Largest class of anti-neoplastics
- General properties/mechanism
- All are electrophilic molecules that covalently modify nucleophilic molecules in cells
- DNA most important adduct (N7 and O6 of Guanine) for anticancer properties
- All are electrophilic molecules that covalently modify nucleophilic molecules in cells
- General types of alkylating agents
- Monofunctional
- Cause single strand DNA breaks
- Bifunctional
- Inhibit DNA replication and transcription by cross-linking DNA
- Subtypes
- Nitrogen mustards
- Nitro-ureas
- Cis-platinum compounds
- Monofunctional
2
Q
Alkylating agents
Sub-types
A
- Nitrogen mustards
- Nitroso-ureas
- CIS platinum compounds
3
Q
Concept alkylation agents
A
- What to alkylate
- Busulfan- has a methyl sulphonic acid leaving the group- this is equivalent of having chlorine (We can’t use the chlorinated version as it is too toxic)
- Must have a nucleophilic centre
- N is nucleophilic, the drug is electrophile, results in alkylation
- Methane sulfonic acid= leaving group = CI atom
- With an alkylating agent on 2 separate sides we can cross-link DNA- causing a blockage of DNA transcription
4
Q
Concept Alkylation
A
- Busulfan= alkylation
- 2 leaving groups
- Selective toxicity
- 5-FU- fluorouracil
- Anti-metabolite
- Fluorine= no leaving group mimic H
5
Q
Complementary base pairs hold the DNA strands
A
- For anti-virals, we either modify the base or sugar- mimic nucleoside
- Base- was an alkylating agent can work
- Chemotherapy- interact with nucleoside
6
Q
Nitrogen mustards
A
- Compound
- Mechlorethamine (mustargen) R=Me
- Hodgekins/lymphomas and chronic leukaemias
- MOPP (Mechlorethamine, vincristine, Oncovin, Procarbazine, Prednisone)
- MOPP regimen
- This agent is not just alkyl group and chlorine- it also has an N which increase efficacy
7
Q
Mechlorethamine (Mustargan)
A
- Mustargan= prototype for the mustards (and other alkylating agents) because of its spectrum of activity
- Toxicities / Mechanism of action
- Highly unstable and reactive- still in use in combination therapy, MOPP 80% response, >50% cure
- Toxicity: nausea and vomiting (N&V). Dose limiting toxicity (DLT) is bone marrow suppression, WBC, esp granulocytes
- Max suppression at 10-12 days, recovery around 42 days
- ADME: t1/2 less than 30 minutes, admin in free flowing catheter
8
Q
Mechlorethamine (mustargan) R=Methyl
Analogs
A
- Chlorambucil
- Melphalan, multiple myeloma
9
Q
Chlorambucil
A
- Chronic lymphocytic leukemia
- Malignant lymphomas
- Cumulative bone marrow toxicity
- Made aromatic- reduction in toxicity
10
Q
SAR optimisation
A
- Replace Me as too reactive- too toxic
- Use amino acid, Phe = Phenylalanine- as in Melphalan
- Again reduce toxicity
- arylated acid= chlorambucil
- Steroid, uracil and phosphamide- cyclophosphamide
11
Q
MOA of mustards
A
- Nitrogen is nucleophillic and removes chlorine to form an aziridine structure
- Aziridine structure is more reactive than chlorine on its own
- Guanine has nucleophillic N which reacts with the aziridine structure
- The removal of the 2nd chlorine atom- form another azirine structure
- This one reacts with the other guanine base to cross-link the DNA
- Driven by an SN2 reaction
12
Q
MOA part 2
A
- SN2 reaction
- Nucleophillic centre
- DNA cross-linked
13
Q
Mustard: replacement of Me by phosphamide: Cyclophosphamide (cytoxan)
A
- Use- malignant lymphomas, various carcinomas, most widely used alkylating agent
- Efficacy: CMF regime increase 7 yr survival from 31% to 49%
- c= Cyclophosphamide
- M= MTX
- F= Fluorouracil
- MOA= activated by CYP450 pro-drug
- Toxicity: better bone marrow recovery better than mustargen
- Treatment: max 10-12 days, recovery 21 days
- ADME- may be administered parenterally, in a large range of doses. Resistant cells may have aldehyde oxidase
14
Q
Cyclophosphamide activation
A
- Activated by P450
- Oxidise molecule and add a hydroxy group
- The aldehyde is then formed
- Allowing cytotoxic to be formed
15
Q
Nitrosoureas
A
- Bis-chloro-nitrosurea (BCNU)- lose nitrogen (forming a positive charge) and attacks anything nucleophillic- this can attack most things with electron density (not just nucleophillic centres)
- Chloroethylcyclohexylnitrosurea -Lomustine (CCNU)
- BCNU + CCNU
- Both used for brain tumour, hodgkin’s disease, melanoma
- lipid soluble (CNS active)
- O6 of Guanine preferred alkylating site, O alkylation (Mustard N alkylation)
- Teratogenic
- Both used for brain tumour, hodgkin’s disease, melanoma
16
Q
MOA- nitrourea
A
- They lose isocynate
- Then lose N2 and H20
- This leaves group with positive charge and chlorine
- Positive charge attacks one base first
- Chlorine alkylates the other base
- This cross-links the DNA
18
Q
BCNU (Carmustin)
A
- Use: primary glioblastoma (with surgery and radiation can increase live span from 20 weeks to 50)
- Toxicity: High, max 28 days: recovery 42 days
- ADME: administered by injection
- Very lipophilic and low ionization at physiological pH- risk of hematological toxicity persist due to storage in the liver
19
Q
Transfer of Me group-alkylation- methylation
Temozolomide
A
- Liver activation results in diazomethane which transfers one methyl group onto the DNA
20
Q
Temozolomide
A
- Discovered at Aston derived from dabcarbazine
- Metabolic activation, dose 200mg/m2 daily for 5 days
- Brain tumour, glioma
- t1/2= 1.2h, orally administered Cmax- 1h
- High CNS penetration
- Active metabolute MTIC
- 5-amino-imidazole-4-carboxamide AIC, is natural constituent of urine
- Methylation of N3 adenine, O6 of guanine
21
Q
CIS- platinium compounds
A
- Cis-platin lead structure
- Least stable chelate
- Most reactive
- Most Toxic
- Platinum creates a double positive compound- 2 DNA bases form a chelate on the Pt
- Not cross-linking
- Any change from cis-platin reduce toxicity
