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41 Cards in this Set

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What are the 3 types of DNA interactive anti-cancer agents?
1) DNA alkylators, 2) DNA strand cutters, & 3) Non-covalent binders
Why are inter-strand cross links more harmful to cells than intra? 
1) prevent strand separation by the replication fork & 2) difficult for endogenous repair mechanisms to fix
What are the 2 mechanisms of DNA strand cutters?
1) superoxide production & 2) direction hydrogen atom abstraction from the sugar backbone
What is the mechanism of the non-covalent binders?
DNA topoisomerase inhibitors - interact with both DNA and protein
Which DNA bases are most nucleophilic?
Adenine and guanine
What are 3 examples of DNA cross linking agents?
1) mechlorethamine, 2) chlorambucil, & 3) clycophosphamide
What is the mechanism of the DNA cross-linking agents?
1) forms two aziridium ions & 2) leaving group is two carbons away--> internal cyclicization
Is DNA electrophyilic or neutrophilic?
neutrophilic
What are 5 functional groups of DNA alkylating agents
1) epoxide, 2) aziridine, 3) aldehyde, 4) imine, 5) alkyl halide
How do nitrogen mustards alkylate DNA?
cross-linking via cyclic aziridine ring
What is the result of DNA alkylation by nitrogen mustards
bisalkylation with a N-7 to N-7 intra or interstrand cross-link
What is the most neucleophilic site on purines?
N-7
Why does this have increased stability?
Lone pair is tied up in resonance with the ring (less reactive)
How do the plantinum II agents alkylate DNA?
cross-linking (intra or inter)
Where do the platinum II agents alkylate DNA?
N-7 position of guanine
What type of agent is cisplatin?
Platinum II (cross-linker)
What is the major form of the product of cisplatin?
Intrastrand
What is the strategy to form the inter-strand cross-links with Platinum II agents?
Make them into dimers separated by 4 carbons
What are the 3 types of DNA interactive pro-drug tiggers?
1) light, 2) oxidation, & 3) reduction
Why is the pro-drug approach better?
Allows selectivity while reducing undesired decomposition of the reactive species before it reaches its target
What is the benefit of dimerization?
allows DNA sequence selectivity
What is the mechanism of the psoralens?
Photolysis triggered modification of thymine
What types of cancer are the psoralens active against?
skin cancer & T-cell lymphoma
Do electrophiles want to gain or lose electrons?
GAIN- attracted to electrons.
What are the two reactive centers of the psoralens?
3-4 and 4'-5' double bonds
What are the properties best for getting between DNA bases and interculating?
flat, aromatic, polycyclic
What is the mechanism of Hexamtylmelamine?
Oxidation triggered; CYP (hepatic) oxidation- addition of -OH -->loss of water--> iminium ion
What electrophilic functional group does hexamethylmelamine use?
iminium ion
What do CYPs do?
Hydroxylate alkylamino groups
What is the general mechanism of the mitomycins?
Reduction triggered DNA modifying
What cancer are the mitomycins used for?
pancreatic
What is the important functional group of the mitomycins?
quinone
What are two properties of a hypoxic tumor?
1) no oxygen (duh), & 2) lots of reductive enzymes---> trigger!!
What is Anthracycline?
(Doxorubicin)- anti-cancer agents containing a quinone and sugar
Mechanism of action of antrhacycline?
mono-reduction resulting in radical production-->DNA monoakylation
What two things can anthracyclines do?
1) DNA intercalation (monoakylation) & 2) DNA topopisomerase II inhibition
Co(III)--> Co(II) is oxidation or reduction?
reduction
What are two functional groups of DNA strand cutters?
1) quinones & 2) metals
What is the mechanism of Bleomycin?
DNA binding metal-based ani-cancer drug that creates superoxide to cut DNA
What does Toposiomerase I do?
Relaxes (unwinds) supercoiled DNA

This is a thermodynamically down hill reaction
What does Toposiomerase II do?
Supercoils DNS using ATP hydrolysis.

This is a thermodynamically uphill reaction