Spring Sem Med Chem Lec 3

Front 1

What are The two currently marketed purine anticancer agents that are both 6-thio analogues of the endogenous purine bases?

Back 1

guanine and purine, also known as inosine.

Front 2

The rate-limiting enzyme in the synthesis of purine nucleotides is what?

Back 2

amidophosphoribosyltransferase

Front 3

Mercaptopurine and Thioguanine Metabolism


What is the first step in the pathway of normal synthesis of AMP and GMP (adenosine and guanine)?

Back 3

amidophosphoribosyltransferase

Front 4

Mercaptopurine and Thioguanine Metabolism


Mercaptopurine and thioguanineare prodrugs and must be converted to what by what, in order to exert what?

Back 4

to ribonucleotides by hypoxanthine guanine phosphoribosyltransferase (HGPRT) before they can exert their cytotoxic actions.

Front 5

Mercaptopurine and Thioguanine Metabolism

Mercaptopurine, acting through a methylatedribonucleotide metabolite, inhibits the target ____ enzyme? What does this lead to what effect?

Back 5

amidophosphoribosyltransferase enzyme, leading to the true antimetabolic effect of lowered AMP and GMP biosynthesis.

Front 6

Mercaptopurine and Thioguanine Metabolism

. A second mechanism of antineoplastic activity for mercaptopurine (and the predominant mechanism for thioguanine) involves the incorporation of ___- and ______- and _____ generated within the tumor cell ubti ___ and____. What does this promote?

Back 6

di- and triphosphatedeoxy- and ribonucleotides generated

DNA and RNA

apoptosis

Front 7

Mercaptopurine and Thioguanine Metabolism

Thiopurines are metabolized by _____ via the ___ enzyme ____ with ______ serving as cofactor.

Back 7

Thiopurines are metabolized by S-methylation via the polymorphic enzyme thiopurine methyl transferase(TPMT) with S-adenosylmethionineserving as cofactor.

Front 8

Mercaptopurine and Thioguanine Metabolism

The methylatedthiopurine bases cannot react with HGPRT and, therefore, cannot form what?

Back 8

the active false ribonucleotides.

Front 9

Mercaptopurine and Thioguanine Metabolism

The active false ribonucleotide 6-thioinosinic acid also is subject to extensive what?

Back 9

TPMT-catalyzed methylation.

Front 10

Mercaptopurine and Thioguanine Metabolism

The S-methyl-6-thioinosinic acid metabolite is a potent inhibitor of the what?

Back 10

amidophosphoribosyltransferase enzyme

Front 11

What are 5 DNA Polymerase/DNA Chain Elongation Inhibitors?

Back 11

Cytaribine

Gencitabine

Cladribine

Clofarabine

Fludaribine phosphate

Front 12

DNA Polymerase/DNA Chain Elongation Inhibitors all must be converted to what?

Back 12

to triphosphate nucleotides before activity is realized

Front 13

DNA Polymerase/DNA Chain Elongation Inhibitors

. As nucleosides, they are actively taken up into cells via a selective what? so tumors deficient in this transporter system will be ___ to these anticancer agents?

Back 13

nucleoside transporter protein

resistant

Front 14

DNA Polymerase/DNA Chain Elongation Inhibitors

In active triphosphate form, they can be mistakenly incorporated into what? What 2 components can it arrest?

Back 14

thus arresting further elongation, and/or inhibiting enzymes essential for DNA synthesis.

Front 15

DNA Polymerase/DNA Chain Elongation Inhibitors

Both cytarabine and gencitabine undergo initial phosphorylation by what? To what? Than is subsequently catalyzed by __ and ___?

Back 15

deoxycytidinekinase to the monophosphate with subsequent phosphorylations catalyzed by pyrimidinemonophosphate and diphosphatekinases

Front 16

DNA Polymerase/DNA Chain Elongation Inhibitors

Cytaribine, an arabinoside, is catabolized ___ an ___ to inactive ____ analogues?

Back 16

is catabolized by cytidine and deoxycytidylate (deoxycytidinemonophosphate) deaminases to inactive uracilanalogues.

Front 17

The significantly longer half-life of gemcitabine (19 hours) compared to conventional cytarabine (3.6 hours) is caused by the ___ action of the ____ metabolite on the potentially degradative ______ enzyme?

Back 17

inhibitory action of the difluorodeoxycytidinetriphosphate metabolite on the potentially degradativedeoxycytidinemonophosphate deaminase enzyme.

Front 18

Mitosos Inhibitors

The mitotic process depends on the structural and functional viability of what? consisting of what?

Back 18

of microtubules- polymeric heterodimers consisting of isotypes of α- and β-tubulinproteins

Front 19

Mitosos Inhibitors

During cell division, tubulin undergoes intense, sporadic, and alternating periods of structural growth and erosion known as what?

Back 19

dynamic instability

Front 20

Mitosos Inhibitors

The proteins alternatively polymerize and depolymerize through what processes?

Back 20

guanosinetriphosphate - and Ca2+- dependent processes.

Front 21

Mitosos Inhibitors

Polymerization results in tubular ____, whereas depolymerization results in the ____of the structure.

Back 21

Polymerization results in tubular elongation, whereas depolymerization results in the shortening of the structure.

Front 22

Mitosos Inhibitors

The frenetic alteration in structure, facilitated by microtubule-associated proteins (MAPs), ultimately allows the formation of the ___ and the attachment to chromosomes that is a prerequisite to cell division

Back 22

mitotic spindle

Front 23

Mitosos Inhibitors

Two classes of mitosis inhibitors currently are marketed for the treatment of cancer are what?

Back 23

taxanes, and vinca alkaloids.

Front 24

Mitosos Inhibitors

Anticancer taxanes initially were isolated from what? but are now produced semisynthetically from an inactive natural precursor found in the leaves of the what? ?

Back 24

the bark of the Pacific yew (Taxusbrevifolia)

European yew (Taxusbaccata) arenewable resource.

Front 25

The vinca alkaloids are found naturally in what?

Back 25

Catharanthusroseus
(periwinkle).

Front 26

Mitosis Inhibitors - Epothilones

What is is a significant drawback to the therapeutic utility of the taxanes?

Back 26

Low water solubility

Front 27

Low water solubility is a significant drawback to the therapeutic utility of the taxanes. This is particularly true of ___. which has a more lipophilic acetate moiety at __ compared to docetaxels more polar hydroxyl group?

Back 27

paclitaxel

c10

Front 28

Paclitaxel must be administered in what kind of vehicle?

Back 28

50% alcohol/50% polyoxyethylated caster oil

Front 29

Paclitaxel must be administered in a vehicle of 50% alcohol/50% polyoxyethylated caster oil, which can lead to anenhanced risk of hypersensitivity reactions (dyspnea,hypotension, angioedema, and uticaria) in patients not pretreated with ___ and ___ antagonits and ___?

Back 29

H1 and H2
antagonists and dexamethasone

Front 30

What happens in order for both taxane anticancer agents which results in drug resistance?

Back 30

high P-glycoprotein–mediated cellular efflux

Front 31

epothilone B has what kind of structure?

Back 31

a 16-membered macrolide structurally unrelated to the taxanes

Front 32

what is being actively investigated for use in a variety of solid tumor and hematologic cancers.

Back 32

epothilone B

Front 33

Epothilone B binds with very high affinity to what binding site?

Back 33

to the taxane binding site on polymerized β-tubulin

Front 34

In addition to enhanced water solubility and a lack of P-glycoprotein affinity, epothilone is more efficiently produced through fermentation with the ____? it has a higher ____ ___

Back 34

myxobacterium (slime bacteria) Sorangiumcellulosumand has a higher antineoplastic potency.

Front 35

What semisynthetic glycosidic derivatives of podophyllotoxin?

Back 35

epipodophyllo toxins

Front 36

The epipodophyllo toxins are semisynthetic glycosidic derivatives of podophyllotoxin, the major component of the what? Isolated from what?

Back 36

resinous podophyllin isolated from the dried roots of the American mandrake or mayapple plant (Podophyllumpeltatum

Front 37

Although epipodophyllo toxins are capable of binding to tubulin and inhibiting mitosis, their primary mechanism of antineoplastic action is what?

Back 37

inhibiting topoisomerase II

Front 38

The RNA transcription processes also are disrupted by the interaction of ___ and ___

Back 38

epipodophyllo toxins with topoisomerase IIα

Front 39

Epipodophyllo toxins are _____ specific

Back 39

Epipodophyllo toxins are cell-cycle specific

Front 40

Epipodophyllo toxins are cell-cycle specific and have their most devastating impact on cells in the __ or __ early phase?

Back 40

S or early G2 phase

Front 41

Camptothecins are ___, extensively ______, amine-containing ______

Back 41

Camptothecins are chiral, extensively conjugated, amine-containing pentacyclic lactones

Front 42

The biological target of camptothecins is what?

Back 42

is topoisomerase I

Front 43

Although the fragmented DNA is capable of resealing in the absence of drug, when DNA replication forks encounter the fragmented DNA, what ends up , killing the cell.?

Back 43

a double-stranded DNA break occurs, killing the cell.

Front 44

What prodrug are considered to be first-line therapy in thetreatment of metastatic colorectal cancer?

Back 44

In combination with fluorouracil, irinotecan is a camptothecin analogue

Front 45

irinotecan Given IV, the drug is slowly bioactivated in the liver through hydrolysis of the __ ___ __?

Back 45

C10
carbamate ester

Front 46

Given IV, the drug is slowly bioactivated in the liver through hydrolysis of the C10
carbamateester. The catalyzing enzyme is a saturablecarboxylesterase known as what?

Back 46

irinote-can-converting enzyme.

Front 47

__ ___is often utilized to silence and regulate genes without changing the original DNA sequence,

Back 47

DNA methylation

Front 48

DNA methylation may be necessary for normal growth from what stages in animals?

Back 48

embryonic

Front 49

Methylation may also be linked to cancer development as methylation of tumor suppressor genes promotes ___and____

Back 49

tumorgenesis and metastasis

Front 50

Cells in the presence of ___incorporate it into DNA during replication and into RNA during transcription,

Back 50

azacitidine

Front 51

Cells in the presence of azacitidineincorporate it into DNA during replication and into RNA during transcription, affecting the way that cell regulation proteins are able to do what?

Back 51

to bind to the DNA/RNA substrate.

Front 52

Inhibition of DNA methylation occurs through the formation of stable complexes between the molecule and what? This results in what?

Back 52

DNA methyltransferase

saturating cell methylation machinery.