DNA Alkylating Drugs

Question 1

T/F: DNA-targeting drugs are generally very toxic so DNA is targeted only in life-threatening diseases

Answer 1

True

Question 2

What is the definition of alkylators

Answer 2

React covalently with DNA bases

Question 3

What are the top four cancers alkylating drugs are prescribed for

Answer 3

Brain tumor (29%), Hodgkin’s Lymphoma (14%), Leukemia (10%), Non-Hodgkin’s Lympoma (10%)

Question 4

What are the top four cancers alkylating drugs are prescribed for

Answer 4

Brain tumor (29%), Hodgkin’s Lymphoma (14%), Leukemia (10%), Non-Hodgkin’s Lympoma (10%)

Question 5

What are key characteristics of DNA alkylators

Answer 5

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

Question 6

What do bifunctional DNA alkylators do

Answer 6

Inter-stand (opposite strands) crosslinking and halt DNA replication resulting in apoptosis

Question 7

What is the MOA of alkylating drugs

Answer 7

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

Question 8

How does the nucleophilicity of the nitrogen effect its MOA

Answer 8

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

Question 9

What are ways to lower the nucleophilicity and electrophilic reactivity of alkylating drugs

Answer 9

Electron withdrawing substituents

Question 10

What are the most nuclephilic DNA sites in alkylation reactions

Answer 10

Nitrogen-7 of guanine, Nitrogen-3 of adenine, Nitrogen-7 of adenine, Nitrogen-3 of guanine, nitrogen-1 of adenine, nitrogen-1 of cytosine

Question 11

What are other nucleophilic sites that can be alkylated

Answer 11

Nitrogen-3 of cytosine, Oxygen-6 of guanine, and phosphate groups

Question 12

What are the consequences of DNA alkylation

Answer 12

Alkylated Guanine no longer hydrogen bonds with cytosine but instead Thymine (mutations), loss of a base (abasic site), Beta elimination causing strand scission

Question 13

What are consequences of interstrand crosslinking of DNA

Answer 13

Doesn’t allow DNA strand seperation, rigidifies DS dNA affecting packing into nucleosomes

Question 14

What are substituents that are added to make alkylating drugs more effective

Answer 14

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)

Question 15

What is the cyclophosphamide MOA

Answer 15

cyclophosphamide is activated by P-450 activation resulting in phosphoramide derivative of nitrogen mustard that is active, spontaneous hydrolyses also creates nitrogen mustard

Question 16

What is the problem with cyclophophamide drugs

Answer 16

Can create acrolein byproduct that is toxic and causes hemorrhagic cysitiits

Question 17

What is the MOA of methanesulfonates

Answer 17

Alkylates guanine Nitrogen-7 causing interstrand crosslinks (SN2 reaction)

Question 18

What is the rate limiting step of normal alkylating agents

Answer 18

Formation of the aziridine ring

Question 19

How are ethylenimines constructed

Answer 19

At least two aziridines are attached to an electron withrdrawing group (attachment of more aziridines does not make a difference)

Question 20

What are the two MOAs of ethylenimines

Answer 20

Hydrolysis to form a free aziridine (major) or direct reasion of azridinium residue (minor)

Question 21

What makes nitrosoureas special in alkylating drugs

Answer 21

Permeate the blood-brain barrier

Question 22

What is the MOA of nitrosoureas

Answer 22

Create a power electrophile, diazonium cation, alkylates guanine at OXYGEN-6

Question 23

What other alkylating drug creates the diazonium cation, important intermediate

Answer 23

Dacarbazine (infusion drug) and Temozolomide (only brain tumor administered orally), MTIC

Question 24

What makes up platinum antineoplastics

Answer 24

Platinum bound to two nitrogens and two leaving groups (planar geometry)

Question 25

What is MOA of Cisplatin

Answer 25

Intrastarand (same strand) crossling resulting in inhibition of transcription (stalling RNA polymerase) and apoptosis