DNA Alkylating Agents (MC) - Block 4 Flashcards
Describe the mechanism of lactone rings?
Love to open due to the ester
What is the mechanism of kinases?
Induces phophorylation of a substrate by taking a phosphate from ATP
What is the most common structure associated with hepatotoxicity?
OH para to an amine
Describe the mechanism of the Michael rx?
Double bond next to ketone will attract neucleophile and irriversible binds to the b-carbon
Describe the metabolism of quinones?
Metabolism through NADPH/CYP450 reductase and production of superoxide radical
What are the cell cycle nonspecific agents (CCNSA)?
Active throught cell cycle:
* Alkylating agents
* Platinum compounds
* Antibiotics
What are the cell cycle specific agents (CCNSA)?
S phase: antimetabolites, topoisomerase inhibitors
M phase: vinca alkaloids, taxanes
G2 phase: Bleomycin, podophyllotoxins
Describe the activity of DNA cross-linking agents?
- Reactive electrophilic structures where nucleophilic groups on DNA base (N7 of guanine) attack electrophilic drug
- Contains 2 DNA bases (crosslinking between 2 DNA strands or single DNA strand)
- Induce mutagenesis and carcinogenesis that promotes and treats cancer
What is the target of DNA cross-linking agents?
Dividing DNA molecules
Describe the chemical structure of nitrogen mustards?
2 Cl atoms that decrease basicity of nitrogen -> unionized at physiological pH
* Formation of very electrophilic aziridinium ion that destroys DNA
Describe the activity of nitrogen mustards and how they crosslink DNA?
- lone pair on N+ attacks b-carbon removing Cl
- Formation of aziridinium ion that is very strained -> can easily open and electrophilic
- Guanine attack aziridinium and covalently binds to molecule
- The other Cl is removed and another guanine covalently binds to aziridinium
- Ion is covalently bound to 2 DNA bases -> damaged DNA -> cell death
Describe the SAR of nitrogen mustard
Nitrogen: provides lone pair for nucleophile attack on b-carbon
a-carbon: maintains proper distance between N and C
b-carbon: gets attacked by lone pair
Cl: EWG, good leaving group, decreases amine pKa
R goup:
* CH3: Release of electrons increasing nucleophilic character of amine; high reactive, nonspecific toxiitiy, no PO activity
* Aryl: Stabilizes amine lone pair decreasing nucleophilic character, decresed reactivity, nonspecific toxicity, and increased PO F
How do you prevent nitrogen mustard decomposition?
Protonating N and/or water -> buffering aqueous solutions to a slightly acidic pH
Avoid neutral or basic water
What is the only aliphati nitrogen mustard?
Mechlorethamine
ADR of mechlorethamine? Antidote?
Contains a reactive methyl group:
* 2% sodium thiosulfate remove chlorine and bind to drug inactivating it (thiosulfate ester) -> used for accidental skin contact
* Severe N/V
Describe the unique structure of melphalan? ADR?
Contains L-Phe because L-aa are transported into cells via aa carrier proteins -> actively be transported into tumor cells via facilitated diffusion
Less N/V than mechlorethamine
Aromatic group makes it less reactive
Describe the structural improvement of bendamustine compared to chlorambucil?
- Imidazole mimics purine -> DNA alkylator and antimetabolite properties
- DNA damage is more extensive/less repairable
- Lower risk for acquired resistance compared to other DNA alkylators
Bendamustine ADRs?
- Myelosuppression
- Hypersensitivity/anaphylaxis
- Skin rx
Pretreat with antihistamine/corticosteroids
How does the structure of cyclophosphamide contribute to its activity?
Phosphate ring that requires liver activation eliminating GI toxicity
Describe activation of cyclophosphamide?
Active products: tertiary, quaternary, and protonated aziridine (less reactive)
Describe the toxicity of cyclophosphamide?
High doses of drug can lead to the formation of toxic metabolites:
* Acrolein: uro and nephrotoxic
* Chloroacetaldehyde: nephro and neurotoxic (not enough glutathione can lead to tox-10% of drug)
What agent can we use for acrolein tox?
Mesna treats urotoxicity not nephrotoxicity by making acrolein more water soluble and excretable
Describe the structure of ifosfamide? How do you compare it to cyclophosphamide?
- Mustard arms are on different nitrogen atoms
- Metabolically activated by CYP3A4
- Less reactive because it doesn’t form a quaternary aziridine
Requires higher doses to achieve same effect as cyclophosphamide, however, high doses lead to more chloroacetadehyde and acrolein
Describe the toxicity of ifosfamide?
Toxic metabolites (60%) -> not enough GSH in the body
* Rx occurs in kidney due to increased water solubility -> higher nephrotoxicity
How to reverse ifosfamide?
GSH-based agents (NAC) which only helps with nephrotox not neurotox
Describe the structure?
Thiotepa: tertiary aziridine (weak alkylator that is less reactive than aziridine
* Can protonate before reacting with DNA but due to sulfer
* PKa is 6 -> very little ionization at physiological pH
* Regioselecitive
ADRs of thiotepa?
- Severe myelosuppression
- Hepato and nephotoxic
- High risk for infection and hemorrhage
What is the active metabolite of thiotepa?
Desulfurated metabolite (TEPA)
What is the purpose of bendamustine’s cemical group?
Imidazole (purine) promots 2 MOAs
What is the purpose for cyclophosphamide chemical group?
Phosphate rng provides liver activation and less GI tox
What is the function of ifosfamide structure?
2 N with Cl chains makes drug less reactiew
Purpose of thiotepa sctructure?
3 tertiary azirdine makes drug less reactive
Describe the MOA of nitroureas?
Unstable and decomposes in aqueous environments:
* Formation of isocynate binds to protein killing it
* Formation of a carbyl cation and clorethyl that causes DNA crosslinking
Describe the PK of carmustine and lomustine?
Very lipophilic useful for brain tumors
* Carmustine IV can’t be in pure water, add 10% ethanol
What is the difference between carmustine and lomustine?
Carmustine: 2 chloroethyl group -> more reactive and higher cross-linking potency
* Degrades within 15 min
* Given as IV or biodegradable wafers (implanted in CNS)
* Pure is solid, decomposed is oil
Lomustine: more stable, PO
ADRs of carmustine and lomustine?
Hemorrhage and massive infection
Pulmonary toxicity (dose-related)
Describe the structure of streptozocin?
No chloroethyl -> less reactive
Contains a sugar
What is the target of streptozocin?
Contains a sugar group (glucopyranose) that targeted to islet cell
* Used for metastatic islet cell carcinoma in the pancreas
ADR of streptozocin?
Highly water soluable (IV in aqueous solution) -> severe or fatal renal toxicity
Despite dffernt MOAs how are procarbazine and triazines similar?
All are O6-methylate guanines
What is the affect of O6 methylate guanines?
Pairs with guanine (mispair) -> point mutation and cell destruction from activation of post relication mismatch repair system
How do patients show resistance to procarbazine and triazines?
Ability to repair damage through O6-alkylguanine DNA alkyltransferase
Interactions associated with procarbazine?
Inhibits MAO and enzymes for ethanol metabolism
What drugs has the highest potential to cause cancer (carcnogenic) out of other alkylating agents?
Procarbazine
.
How does procarbazine methylate guanine?
Through free radical mechanism (radical methyl methyltes guanine)
How does dacarbazine metylate guanine?
Formation of methyl carbocation from diazomethane metylates DNA
ADR of dacarbazine?
Hepatotoxicity
Potent vesicant (avoid extravasation upon administration)
How does temozolide differ from procarbazine and triazines?
Nonenzymatic to get activated
* Myelosuppression in women (unable to clear as effectively)
ADR of busulfan?
Severe bone marrow hypoplasia and myelosuppression
MOA of busulfan?
Does not require activate: sulfonate group get attacked by DNA bases -> cross linkage
MOA of organoplatinum?
Electron-deficient metal atom that is a magnet for electron rich DNA nucleophiles:
* Pt = electron deficient (ligands donate electrons Pt -> net charge of 0)
* When R=Cl -> tumor cells are Cl poor -> facilitated
* When R is displaced by water, Pt has a positive charge -> attck DNA nucleophile
* Crosslinks DNA with 2+
What is the ideal confirmation of organoplatinum?
Cis: DNA repair mechanism can’t correct damage from cis conformation -> apoptosis
Describe the SAR of organoplatinum?
- Pt
- 2 electron releasing groups that are displaced by H2O (impacts reactivity, potecy, and toxicity)
- Permanent amine ligands stabilize DNA complex by binding to DNA phosphate
- DACH ring decreases resistance
Describe the structure?
Cisplatin: Cl are reactive -> rapid hydration and shorter half-life
ADR of cisplatin? How do you the treat?
Kidney elimination -> highly nephrotoxic
* Give Cl-containig solutions, saline, mannitol (promotes excretion)
* Give sodium thiosulfat (accumulates in ren tubules, neutralizing active drug) -> high PPB therefore not for plasma or dialysis
Reactive Chlorides -> ototoxicity (concetrated in cochlea)
* Pretreat with amifostine that gets activated by alkaline phosphatase (higher activity in tissue) and removes Cl reactants
Severe emetogen (vomiting)
Who do you make cisplatin less reactive?
Remove Cl
How does carboplatin differ from cisplatin?
Cyclic ring makes drug less potent and milder side effects
Most significant ADR of carboplatin?
Suppression of platelets and WBCs
* Renal excretion but not nephrotoxic (less reactive)
How is oxaliplatin an improvement from cisplatin?
Loses oxalate dianion instead of Cl
* Excreted in kidneys but not nephrotoxic
What are the disadvantages of oxaliplatin?
Oxalate chelates intracellular Ca2+ -> peripheral neuropathy
* Can give Ca2+ and Mg2+ salts to reduce
* Ca2+ inhibits voltage-gated sodium channels in sensory nerve cells
How does oxaliplatin contribute to cytotoxicity?
Ring extends into major groove of DNA
* Also produces a narrower minor groove (amine forms H bond with guanine-O6) -> Less likely to be recognized by mismatch repair proteins (MMR) -> lack resistance
ADR and considerations of oxaliplatin use?
Decomposes in alkaline media -> avoid coadministeratin with drugs that may raise pH
ADR: pulmonary fibrosis
Are DNA alkylying agenets cell cycle specific?
No
