DNA Alkylating Drugs Flashcards
(25 cards)
T/F: DNA-targeting drugs are generally very toxic so DNA is targeted only in life-threatening diseases
True
What is the definition of alkylators
React covalently with DNA bases
What are the top four cancers alkylating drugs are prescribed for
Brain tumor (29%), Hodgkin’s Lymphoma (14%), Leukemia (10%), Non-Hodgkin’s Lympoma (10%)
What are the top four cancers alkylating drugs are prescribed for
Brain tumor (29%), Hodgkin’s Lymphoma (14%), Leukemia (10%), Non-Hodgkin’s Lympoma (10%)
What are key characteristics of DNA alkylators
All are ELECTROPHILES- forming covalent bonds with DNA nucleophilic sites/ modification can lead to DNA depurination, stand scission, trigger DNA repair/ DNA alkylation results in mutations and can cause secondary cancer after remission
What do bifunctional DNA alkylators do
Inter-stand (opposite strands) crosslinking and halt DNA replication resulting in apoptosis
What is the MOA of alkylating drugs
Nucleophillic nitrogen increases the reactivity of alkylating arms, certain substiutients leave causing cycleization of nitrogen to create the aziridinium cation, the aziridinium cation is attacked by nucleophillic bases of DNA causing the first adduct, the process is repeated for crosslinked adduct
How does the nucleophilicity of the nitrogen effect its MOA
If the nucleophilicity is too high the drugs becomes too reactive and too toxic, if the nucleophilic nitrogen is too weak there is no activity
What are ways to lower the nucleophilicity and electrophilic reactivity of alkylating drugs
Electron withdrawing substituents
What are the most nuclephilic DNA sites in alkylation reactions
Nitrogen-7 of guanine, Nitrogen-3 of adenine, Nitrogen-7 of adenine, Nitrogen-3 of guanine, nitrogen-1 of adenine, nitrogen-1 of cytosine
What are other nucleophilic sites that can be alkylated
Nitrogen-3 of cytosine, Oxygen-6 of guanine, and phosphate groups
What are the consequences of DNA alkylation
Alkylated Guanine no longer hydrogen bonds with cytosine but instead Thymine (mutations), loss of a base (abasic site), Beta elimination causing strand scission
What are consequences of interstrand crosslinking of DNA
Doesn’t allow DNA strand seperation, rigidifies DS dNA affecting packing into nucleosomes
What are substituents that are added to make alkylating drugs more effective
Addition of a phenyl ring (diminsh nitrogen nucleophilicity/), Carboxylic acid (stabilize the comound) carbon chains (keeps the carboxylic far away from phenyl ring to limit electron withdrawing features)
What is the cyclophosphamide MOA
cyclophosphamide is activated by P-450 activation resulting in phosphoramide derivative of nitrogen mustard that is active, spontaneous hydrolyses also creates nitrogen mustard
What is the problem with cyclophophamide drugs
Can create acrolein byproduct that is toxic and causes hemorrhagic cysitiits
What is the MOA of methanesulfonates
Alkylates guanine Nitrogen-7 causing interstrand crosslinks (SN2 reaction)
What is the rate limiting step of normal alkylating agents
Formation of the aziridine ring
How are ethylenimines constructed
At least two aziridines are attached to an electron withrdrawing group (attachment of more aziridines does not make a difference)
What are the two MOAs of ethylenimines
Hydrolysis to form a free aziridine (major) or direct reasion of azridinium residue (minor)
What makes nitrosoureas special in alkylating drugs
Permeate the blood-brain barrier
What is the MOA of nitrosoureas
Create a power electrophile, diazonium cation, alkylates guanine at OXYGEN-6
What other alkylating drug creates the diazonium cation, important intermediate
Dacarbazine (infusion drug) and Temozolomide (only brain tumor administered orally), MTIC
What makes up platinum antineoplastics
Platinum bound to two nitrogens and two leaving groups (planar geometry)
