Med Chem Spring Lec 1

Front 1

The causes of cancer are many and varied (e.g., chemical, environmental, viral, and mutagenic), but all ultimately lead to an aberration in the expression of what?

Back 1

protooncogenes

Front 2

What are protooncogenes?

Back 2

the products of which control normal cell life

Front 3

When protoonco genes mutate they become what?

Back 3

oncogenes

Front 4

Oncogenes (e.g., myc and ras) can either overexpress or underexpress what? What does this result in?

Back 4

regulatory biochemicals, resulting in preferential and accelerated cellular growth.

Front 5

Can tumor suppressor genes (e.g., anti-oncogenes like p53, p21,pINK4A, and retinoblastoma) be inhibited?

Back 5

yes

Front 6

Which structure is this?

Back 6

Sulfur mustard

ex. mustard gas

Front 7

What is this structure?

Back 7

Nitrogen mustard

Front 8

What is the structure on the right called?

Back 8

Aziridinium Ion

Front 9

What is the simplest therapeutic nitrogen mustard?

Back 9

Mechlorethamine(Mustargen)

Front 10

How is Mechlorethamine(Mustargen) administered as?

Back 10

an iv solution HCl sal

Front 11

Mechlorethamine(Mustargen) is a severe ___? What kind of agent?

Back 11

Is is a severe vesicant (blistering agent, like the sulfur mustards)

Front 12

In the case of skin contact, mechlorethamine is deactivated by treatment with What?

Back 12

sodium thiosulfatesolution.

Front 13

What is the first structure in this reaction?

Back 13

Mechlorethamine(Mustargen)

Front 14

Melphalanand Chlorambucilhave aromatic rings which stabilize what? What does it slow the formation of? What does this inturn reduce?

Back 14

the nitrogen lone pair and slow the formation of the aziridinium ion – reducing side effects and increasing distribution in the body.

Front 15

The carbamate functional group in Estramustine offers what?

Back 15

resonance stabilization to nitrogen lone pair.

Front 16

The carbamate functional group in Estramustineoffers resonance stabilization to nitrogen lone pair. The estradiol carrier aids in what?

Back 16

selectively delivering drug to steroid-dependant prostate tissue.

Front 17

What are two examples of Nitrogen Mustard prodrugs?

Back 17

Cyclophosphamide and ifosphamide

Front 18

Cyclophosphamideand ifosphamide are prodrugs which require what?

Back 18

bioactivation by liver metabolism

Front 19

Cyclophosphamideand ifosphamide are prodrugs which require bioactivation by liver metabolism . This means lower what?

Back 19

This means lower GI tox and less nonspecific tox overall,

Front 20

Cyclophosphamideand ifosphamide are prodrugs which require bioactivation by liver metabolism . This means lower GI tox and less nonspecific tox overall, but the acrolein formed during bioactivation is very what? What does this cause?

Back 20

very electrophilic and causes extensive damage to the cells of the kidney and bladder when excreted.

Front 21

The tertiary aziridine in Thiotepa is much less reactive than what? How does it effect this compound?

Back 21

quaternary aziridine and thus this compound is a very weak alkylator.

Front 22

What are these 2 structures?

Back 22

Melphalan and Chlorambucil

Front 23

What are these two structures?

Back 23

Cyclophosphamide and ifosphamide

Front 24

What is this structure?

Back 24

Thiotepa

Front 25

The primary metabolism of cyclophosphamide is by which enzyme subtype?

Back 25

CYP2B6 liver enzyme subtype.

Front 26

CYP3A4 primarily acts to yield what? It results in addational ___ and ____ ___ ___

Back 26

inactive metabolites and results in additional neuro- and nephrotoxic metabolite chloroactealdehyde.

Front 27

Ifosphamide metabolism is similar to what? What is different?

Back 27

cyclophosphamide, but enzyme subtypes involved are different.

Front 28

_____ is a very efficient alklyator of sulfhydryl containing proteins in bladder cells?

Back 28

Acrolein

Front 29

To minimize the risk of bladder toxicity from acrolein what should be done?

Back 29

fluids should be forced and the bladder irrigated.

Front 30

What is also is available as adjuvant therapy in case of overt toxicity or as a prophylactic protectant?

Back 30

Mesna(Mesnex)

Front 31

Mesna concentrates in what? What does it prevent?

Back 31

the bladder and will prevent damage to those cells

Front 32

Mesna concentrates in the bladder and will prevent damage to those cells. It does not concentrate to any appreciable extent in the nephron and, therefore, is not good protection against what?

Back 32

cyclophosphamide-induced nephrotoxicity.

Front 33

The nitrosoureas are what kind of structures? Where do they decompose?

Back 33

The nitrosoureas are unstable structures that decompose readily in the aqueous environment of the cell.

Front 34

The nitrosoureas are unstable structures that decompose readily in the aqueous environment of the cell. Nonenzymatic fragmentation is stimulated by what?

Back 34

by the loss of proton from the urea moiety.

Front 35

DNA Cross-Linking Agents Nitrosoureas

Cyclization of the resultant anion to an unstable oxazolidine what pathway?

Back 35

pathway A

Front 36

DNA Cross-Linking Agents - Nitrosoureas

Cyclization of the resultant anion to an unstable oxazolidine (pathway A) is followed by what?

Back 36

decomposition to vinyldiazotic acid and a substituted isocyanate, both of which release a gaseous fragment (nitrogen and carbon dioxide, respectively) to generate cytotoxic electrophiles.

Front 37

DNA Cross-Linking Agents - Nitrosoureas

Vinyl carbocation, acetaldehyde, and 2-chloro-ethylamine generated from what? What are they all capable of?

Back 37

generated from the 2-chloroethylisocyanate moiety of carmustine are all capable of alkylating DNA.

Front 38

DNA Cross-Linking Agents - Nitrosoureas


A second decomposition mechanism (pathway B) ultimately produces what? What is it capable of?

Back 38

electrophilic 2-chloroethylcarbocation capable of DNA alky-lation at guanine N7 and O6, as well as an isocyanate that can carbamylate amino acid residues (e.g., Lys).

Front 39

Both carmustineand lomustine are highly what? What can they not be administered in?

Back 39

are highly lipophilic and therefore cannot be administered in a purely aqueous solution.

Front 40

Both carmustineand lomustine are highly lipophilic and therefore cannot be administered in a purely aqueous solution. What is used instead?

Back 40

A 10% ethanol solution is used instead

Front 41

Carmustine degrades within ___ minutes of admin?

Back 41

15

Front 42

Lomustine is stable enough to be offered in what kind of formulation?

Back 42

capsule

Front 43

The glucopyranose moiety of streptozocinconfers both what?

Back 43

islet cell specificity and high water solubility to this nitrosourea-based antineoplastic.

Front 44

The glucopyranose moiety of streptozocinconfers both islet cell specificity and high water solubility to this nitrosourea-based antineoplastic. As a result, it is used exclusively in what?

Back 44

metastatic islet cell carcinoma of the pancreas and is administered IV in D5W or normal saline.

Front 45

The glucopyranose moiety of streptozocin Lacks the 2-chloroethyl substituent of carmustine and lomustine which makes it much less reactive as what?

Back 45

less reactive as a DNA alky-lating agent

Front 46

Procarbazineand the triazenes (dacarbazineand temozolomide) act by different mechanisms, but they all exert what kind of effect?

Back 46

exert an antineoplastic effect through the O6 methylation of guanine nucleotides.

Front 47

O6-methyl-guanine pairs preferentially with what?

Back 47

thymine

Front 48

O6-methyl-guanine pairs preferentially with thymine, and these “mispairs” prompt what during what?

Back 48

prompt point mutations during subsequent DNA replication cycles

Front 49

O6-methyl-guanine pairs preferentially with thymine, and these “mispairs” prompt point mutations during subsequent DNA replication cycles and trigger what through what?

Back 49

cell destruction through the activation of the normal postreplication mismatch repair (MMR) system.

Front 50

Patients who are able to repair this damage through the action of O6 alkylguanine-DNA-alkyltransferase, which transfers the offending ___ group to a ___ residue on ____ protein?

Back 50

CH3 group to a Cys residue on the alkyltransferase protein,

Front 51

Patients who are able to repair this damage through the action of O6 alkylguanine-DNA-alkyltransferase, which transfers the offending CH3 group to a Cys residue on the alkyltransferase protein will exhibit what?

Back 51

will exhibit resistance to these agents, whereas those who under express this protein should respond well

Front 52

Because the alkyltransferase is irreversibly inactivated in the DNA rescue process, what is at risk?

Back 52

enzyme depletion (and subsequent loss of DNA repair capability) is a significant risk.

Front 53

Procarbazinemetabolism involves which two enzymes?

Back 53

CYP1A and CYP2B enzymes

Front 54

Procarbazinemetabolism involves CYP1A and CYP2B enzymes, and DNA alkylation operates through what mechanism?

Back 54

a free radical mechanism.

Front 55

Procarbazinemetabolism involves CYP1A and CYP2B enzymes, and DNA alkylation operates through a free radical mechanism. The major degradation pathway involves what?

Back 55

benzylic oxidation of azoprocarbazine

Front 56

he major degradation pathway involves benzylic oxidation of azoprocarbazine, producing what? What does this generate? Through what intermediate?

Back 56

methylhydrazine that generates a methyl radical through an unstable diazene intermediate.

Front 57

The major degradation pathway involves benzylic oxidation of azoprocarbazine, producing methylhydrazine that generates a methyl radical through an unstable diazene intermediate. In addition to O6 methylation, the reactive methyl radical formed can alkylate what positions of guanine?

Back 57

the C8 and N7 positions of guanine.

Front 58

In contrast to procarbazine, the triazenes (dacarbazine and temozolamide) methylate what, how?

Back 58

methylate DNA guanine via diazomethane and/or methyl carbocation generated in situ

Front 59

temozolomide is converted to the diazomethane precursor _____

Back 59

MTIC

Front 60

the conversion of dacarbazine to MTIC depends on the action of what enzymes?

Back 60

CYP1A1and CYP1A2 enzymes, with a smaller contribution by CYP2E1

Front 61

What positions of guanine are the most vulnerable to triazenemethylation?

Back 61

O6 and N7

Front 62

Altretamine is believed to damage what cells?

Back 62

damage tumor cells

Front 63

Altretamine is believed to damage tumor cells through the production of what?

Back 63

the weakly alkylating species formaldehyde, a product of CYP450-mediated N-demethylation.

Front 64

Altretamine is administered how?

Back 64

orally

Front 65

Administered orally, altretamine is extensively metabolized on which pass?

Back 65

1st

Front 66

Administered orally, altretamine is extensively metabolized on first pass, producing what two metabolites?

Back 66

primarily mono- and didemethylated metabolites.

Front 67

Administered orally, altretamine is extensively metabolized on first pass, producing primarily mono- and didemethylated metabolites. Additional demethylation reactions occur in tumor cells, releasing what?

Back 67

formaldehyde in situ before the drug is excreted in the urine.

Front 68

The carbinolamine (methylol)intermediates of CYP450-mediated metabolism also can generate what species?

Back 68

electrophiliciminiumspecies

Front 69

The carbinolamine (methylol)intermediates of CYP450-mediated metabolism also can generate electrophiliciminium species that are capable of reacting covalently with what?

Back 69

DNA guanine and cytosine residues as well as protein.

Front 70

Chemically, busulfan is classified as an ____?

Back 70

alkylsulfonate.

Front 71

Chemically, busulfan is classified as an alkylsulfonate. One or both of the methylsulfonate ester moieties can be displaced by what? What does this lead to?

Back 71

the nucleophilic N7 of guanine, leading to mono alkylated and cross-linked DNA.

Front 72

What are effects of busulfan?

Back 72

Serious bone marrow hypoplasia and myelosuppression are possible with this agent

Front 73

recovery from busulfan-induced pancytopenia can take up to how long?

Back 73

2 years