Alkylating and Metallating Agents (Parang)

Name a key nucleophilic group found on DNA bases

N^7 of guanine

Explain why toxic ADRs occur w/ alkylating agents

They can alkylate proteins

Describe the bond formed from DNA cross-linking agents

irreversible alkylation

Describe how an alkylated guanine can result in miscoding

it prefers enol tautomer rather than keto tautomer → will interact with thymine instead of cytosine

At physiological pH, nitrogen mustards & aziridine-mediated alkylators are ionized or unionized?

Unionized

If nitrogen mustards & aziridine-mediated alkylators are unionized at physiologic pH, how do they eventually become charged?

The unionized amine allows formation of highly electrophilic aziridinium ion —> very reactive against DNA

Name the drug class that forms an aziridinium ion to target DNA

nitrogen mustards

What structural difference determines the types of characteristics a nitrogen mustard has?

if the third group (R) attached to the amino nitrogen is alipathic or aromatic

alipathic vs aromatic nitrogen mustards: which reacts faster?

alipathic

Name the only allopathic nitrogen mustards available on the US market using IV administration

Mechlorethamine

What agent is used to inactivate mechlorethamine ?

2% Sodium thiosulfate (creates inactive and water-soluble thiosulfate ester that can be washed away)

Name the most commonly used alkylating agent

Cyclophosphamide

explain why cyclophosphamide has lower toxicity compared to other alkylating agents

It is a non-toxic prodrug that is not activated until the liver, which reduces GI toxicity and nonspecific toxicity

What does cyclophosphamide produce ? And what is the resulting toxicity?

Acrolein which is associated with bladder toxicity (hemorrhagic cystitis)

Name the agent that can be used to reduce acrolein accumulation in the bladder

Mesna

Explain why aromatic nitogen mustards have a slower reaction rate and the resulting fx

the aromatic nitrogen substituent stabilizes the lone pair through resonance → allows drug to be taken via oral administration & attenuates the ADRs

Alipathic vs aromatic nitrogen mustard: which has fewer ADRs? why?

aromatic d/t increased stability from resonance

Alipathic vs aromatic nitrogen mustard: which can be admin oral?

aromatic nitrogen mustards

Which aromatic mustard is less reactive and has less toxicity

Chlroambucil

Which aromatic mustard mimics phenylalanine?

Melphalan

Which aromatic mustard contains a uracil ring (mimics nucleic acid base) ?

Uracil mustard

Which aromatic mustard is transported into cells via transport protein?

Melphalan

name the nitrogen mustard that is a tertiary aziridine and the resulting fx of this structural difference

thiotepa ; makes it less reactive

Explain the cause of ADRs from nitrosoureas

Produces isocyanate which acts as a carbamoylating agent that reacts with lysine residues, leading to alterations in protein function

Name a nitrosourea example that can be admin orally

lomustine

MOA of DNA methylators

O⁶ methylation of guanine nucleotides, which pair preferentially with thymine → triggers cell death

Which class of alkyating agent works by producing another alkyating agent?

nitrosoureas

nitrosoureas cause ____ crosslinking

interstrand

which DNA methylator is a prodrug?

dacarbazine

name the two drugs that are DNA methylators

procarbazine and dacarbazine

Which drug class works via production of a methyl radical that is highly reactive?

DNA methylators

dacarbazine is decomposed to form what?

methyldiazonium ion

Name the most toxic anticancer drug that is also a prodrug?

mitomycin C

name the drug that is classified as an alkyl sulfonate

busulfan

Which organoplatinium drug is a prodrug?

cisplatin

What has to happen to organoplatnium complexes prior to interacting with DNA? Why does this happen?

the electron donating ligand (Cl) has to be displaced via nucleophilic attack by water - this happens because water is a better leaving group than Cl, which will optimize the reaction

in which cells is cisplatin activated in?

cells with low chloride ion concentration

concerns with cisplatin

highly nephrotoxic

Which agent is used to mitigate the nephrotoxicity caused by cisplatin?

amifostine

Name a cytoprotective agent that is a prodrug and what toxicity it mitigates

amifostine - mitigates the nephrotoxicity linked to cisplatin

Name the advantage of carboplatin over cisplatin

has no renal toxicity

explain why carboplatin is less potent than cisplatin

forms the same cytotoxic hydrated intermediate but at a much slower rate

Which cisplatin analogue loses a oxalate in vivo to form DACH platinium analogs

oxaliplatin

Which cisplatin analog is derrived from picoline ring (2-methylpyridine) associated w/ platinium atom ?

picoplatin

Which cisplatin analogue has the least ADRs?

carboplatin

Based off the functional group (green), what is the drug class?

nitrogen mustards and aziridine-mediated alkylators

Based off the functional group (green), what is the drug class?

nitrogen mustards and aziridine-mediated alkylators

Based off the functional group (green + yellow ), what is the drug class?

nitrosoureas

Name the FG in green

urea

Name the FG in yellow

urea

Based off the functional group (green), what is the drug class?

organoplatinium complexes

Based off the functional group (green), what is the drug class?

organoplatinium complexes

Based off the functional group (green), what is the drug class?

DNA methylators