532 - Med Chem Ii - Exam Ii - Dna Interactive Drugs

Front 1

What are the 3 types of DNA interactive anti-cancer agents?

Back 1

1) DNA alkylators, 2) DNA strand cutters, & 3) Non-covalent binders

Front 2

Why are inter-strand cross links more harmful to cells than intra? 

Back 2

1) prevent strand separation by the replication fork & 2) difficult for endogenous repair mechanisms to fix

Front 3

What are the 2 mechanisms of DNA strand cutters?

Back 3

1) superoxide production & 2) direction hydrogen atom abstraction from the sugar backbone

Front 4

What is the mechanism of the non-covalent binders?

Back 4

DNA topoisomerase inhibitors - interact with both DNA and protein

Front 5

Which DNA bases are most nucleophilic?

Back 5

Adenine and guanine

Front 6

What are 3 examples of DNA cross linking agents?

Back 6

1) mechlorethamine, 2) chlorambucil, & 3) clycophosphamide

Front 7

What is the mechanism of the DNA cross-linking agents?

Back 7

1) forms two aziridium ions & 2) leaving group is two carbons away--> internal cyclicization

Front 8

Is DNA electrophyilic or neutrophilic?

Back 8

neutrophilic

Front 9

What are 5 functional groups of DNA alkylating agents

Back 9

1) epoxide, 2) aziridine, 3) aldehyde, 4) imine, 5) alkyl halide

Front 10

How do nitrogen mustards alkylate DNA?

Back 10

cross-linking via cyclic aziridine ring

Front 11

What is the result of DNA alkylation by nitrogen mustards

Back 11

bisalkylation with a N-7 to N-7 intra or interstrand cross-link

Front 12

What is the most neucleophilic site on purines?

Back 12

N-7

Front 13

Why does this have increased stability?

Back 13

Lone pair is tied up in resonance with the ring (less reactive)

Front 14

How do the plantinum II agents alkylate DNA?

Back 14

cross-linking (intra or inter)

Front 15

Where do the platinum II agents alkylate DNA?

Back 15

N-7 position of guanine

Front 16

What type of agent is cisplatin?

Back 16

Platinum II (cross-linker)

Front 17

What is the major form of the product of cisplatin?

Back 17

Intrastrand

Front 18

What is the strategy to form the inter-strand cross-links with Platinum II agents?

Back 18

Make them into dimers separated by 4 carbons

Front 19

What are the 3 types of DNA interactive pro-drug tiggers?

Back 19

1) light, 2) oxidation, & 3) reduction

Front 20

Why is the pro-drug approach better?

Back 20

Allows selectivity while reducing undesired decomposition of the reactive species before it reaches its target

Front 21

What is the benefit of dimerization?

Back 21

allows DNA sequence selectivity

Front 22

What is the mechanism of the psoralens?

Back 22

Photolysis triggered modification of thymine

Front 23

What types of cancer are the psoralens active against?

Back 23

skin cancer & T-cell lymphoma

Front 24

Do electrophiles want to gain or lose electrons?

Back 24

GAIN- attracted to electrons.

Front 25

What are the two reactive centers of the psoralens?

Back 25

3-4 and 4'-5' double bonds

Front 26

What are the properties best for getting between DNA bases and interculating?

Back 26

flat, aromatic, polycyclic

Front 27

What is the mechanism of Hexamtylmelamine?

Back 27

Oxidation triggered; CYP (hepatic) oxidation- addition of -OH -->loss of water--> iminium ion

Front 28

What electrophilic functional group does hexamethylmelamine use?

Back 28

iminium ion

Front 29

What do CYPs do?

Back 29

Hydroxylate alkylamino groups

Front 30

What is the general mechanism of the mitomycins?

Back 30

Reduction triggered DNA modifying

Front 31

What cancer are the mitomycins used for?

Back 31

pancreatic

Front 32

What is the important functional group of the mitomycins?

Back 32

quinone

Front 33

What are two properties of a hypoxic tumor?

Back 33

1) no oxygen (duh), & 2) lots of reductive enzymes---> trigger!!

Front 34

What is Anthracycline?

Back 34

(Doxorubicin)- anti-cancer agents containing a quinone and sugar

Front 35

Mechanism of action of antrhacycline?

Back 35

mono-reduction resulting in radical production-->DNA monoakylation

Front 36

What two things can anthracyclines do?

Back 36

1) DNA intercalation (monoakylation) & 2) DNA topopisomerase II inhibition

Front 37

Co(III)--> Co(II) is oxidation or reduction?

Back 37

reduction

Front 38

What are two functional groups of DNA strand cutters?

Back 38

1) quinones & 2) metals

Front 39

What is the mechanism of Bleomycin?

Back 39

DNA binding metal-based ani-cancer drug that creates superoxide to cut DNA

Front 40

What does Toposiomerase I do?

Back 40

Relaxes (unwinds) supercoiled DNA

This is a thermodynamically down hill reaction

Front 41

What does Toposiomerase II do?

Back 41

Supercoils DNS using ATP hydrolysis.

This is a thermodynamically uphill reaction