Lec 16-17

DNA Alkylation

Covalently modify DNA

Can be same(intra) or different strands(inter)

Interstrand cross-links are the most harmful bc they stop replication by preventing strand separation

ex: mustargen, cisplatin, enediynes, mitomycin C and other quinone containing agents such as the anthracyclines

DNA Strand cutters

Cutting action is result of two reactions:

a)Superoxide production

2)Grabbing hydrogen atom

Non-Covalent Binders

Reversible

ex: topoismoerase inhibtors

What drug is this and how does it work

Mustargen

DNA Alkylator, reacts twice, cross linking

What drug is this and how does it work

Cisplatin

Reacts twice, alkylating agent

What drug is this and how does it work

mitomycin

Quinone is the ring with the double bonds

Alkylating agent

What kind of drug is this and how does it work

Anthracyclines

Tetracyclic

Single electron reduction- to form monoaduct and can have reversible mechanisms and inhibit DNA topoisomerase

What drug is this and how does it work

Bleomycin

Uses Nitrogens to coordinate iron, then leads to a hydroxyl radical to cur DNA

“Pseduo enzyme”

What drug is this and how does it work 

Calicheamicin- enediyes  

Bergman Cyclization forms a radical but need heat

What drug is this and how does it work

Mylotarg (Enediynes)- Calicheamicin and antibody conjugate

Forms a radical via ring formation at 37 degrees C - Bergman Cyclization

Topoisomerase I inhibitors

Irinotecan

Topotecan

Camptothecin

What drug is this and how does it work

Irinotecan-Prodrug

Topo 1 inhibitor

What drug is this and how does it work

Topotecan- first approved for oral use

Topo 1 inhibitor

What drug is this and how does it work

Camptothecin

Low solubility- D and E rings are the most important for reacting with topoisomerase I, especially the E ring

Topo 1 inhibtor

Topo 2 inhibtors

Podophyllotoxin, Eptoposide, Teniposide

Mitaxntrone, Pixantrone

What drug is this and how does it work

Podophyllotoxin

Topo II inhibtor

what drug

Eptoposide

Topo II inhibtor

what drug

Teniposide

Topo 2 inhibtor

Mitoxantrone

Topo 2 inhibtor

Pixantrone

Topo 2 inhibtor

3 ways pro drugs are triggered

Light

Oxidation

Reduction

mitomycin C MOA

Quinone is reduced and an interstrand cross-link forms

psoralens moa

idk

hexamethylmelamine (HMM) MOA

the oxidative processing that converts HMM into a DNA crosslinking agent is very common to human metabolism of foreign compounds (referred to sometimes as xenobiotics).

Activated by oxidation