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