Med Chem Spring Lec 2

Front 1

What structure is this?

Back 1

Cisplatin
(Square-planar geometry

Front 2

Organoplatinum antineoplastic agents contain what and act as what?

Back 2

an electron-deficient platinum atom that acts as a magnet for electron-rich DNA nucleophiles.

Front 3

The platinum atom in cisplatin is associated with what two functional group ligands?

Back 3

with two chlorine ligands and two ammonia ligands

Front 4

Platinum is inherently electron deficient, but the net charge on the organometallic complex is ____, why?

Back 4

zero because of the contribution of electrons by two of the four ligands (the chlorines) bound to platinum.

Front 5

The ammonia-platinum bonds in cisplatin are what kind of bonds?

Back 5

dipolar bonds (aka dative covalent bond, coordinate bond) is a kind of 2-center, 2-electron covalent bond in which the two electrons derive from the same atom.

Front 6

Like nitrogen mustards, organoplatinum complexes are ____ and can accept electrons from two ___ ___

Back 6

are bifunctional and can accept electrons from two DNA nucleophiles.

Front 7

All of the currently marketed organoplatinum anticancer agents are Pt(II) complexes with what kind of geometry?

Back 7

square-planar

Front 8

Cisplatin Bioactivation and Intrastrand DNA Cross-Linking

The chloride ions in cisplatin are particularly important in its action as a drug. They are relatively stable when the drug is what?

Back 8

is outside the cell, where the chloride concentration
is normally high

Front 9

The chloride ions in cisplatin are particularly important in its action as a drug. They are relatively stable when the drug is outside the cell, where the chloride concentration
is normally high. But when the drug gets inside the cell and the chloride concentration drop, what happens to the cisplatin?

Back 9

cisplatin loses its two chlorides, and they are replaced by water molecules

Front 10

The chloride ions in cisplatin are particularly important in its action as a drug. They are relatively stable when the drug is outside the cell, where the chloride concentration
is normally high. But when the drug gets inside the cell and the chloride concentration drops, cisplatin loses its two chlorides, and they are replaced by water molecules. What does this result in formation of?

Back 10

mono- and di-hydrated cisplatins are the cytotoxic agents which give cisplatin its anticancer effect.

Front 11

Cisplatin Bioactivation and DNA Cross-Linking

Because the original chlorine anions leave the metal, the hydrated organoplatinum molecule has what kind of charge? What readily happens to it?

Back 11

has a net positive charge and is readily attacked by DNA nucleophiles (e.g., the N7 of adjacent guanine residues

Front 12

Because the original chlorine anions leave the metal, the hydrated organoplatinum molecule has a net positive charge and is readily attacked by DNA nucleophiles (e.g., the N7 of adjacent guanine residues). What is the net result

Back 12

is a major change in DNA conformation such that base pairs that normally engage in hydrogen-bond formation are not permitted to interact.

Front 13

Because the original chlorine anions leave the metal, the hydrated organoplatinum molecule has a net positive charge and is readily attacked by DNA nucleophiles (e.g., the N7 of adjacent guanine residues). The net result is a major change in DNA conformation such that base pairs that normally engage in hydrogen-bond formation are not permitted to interact.

What how are the 2 amine ligands of the complex bound? What do they stabilize? By doing what?

Back 13

but they do stabilize the cross-linked DNA-platinum complex by forming strong ion–dipole bonds with the anionic (negatively charged) phosphate residues on DNA.

Front 14

What is this structure?

Back 14

cisplatin geometry predisposed to crosslink DNA

Front 15

What is this structure?

Back 15

transplatin

Front 16

Because of the cis geometry of the chlorine-platinum bonds, cisplatin easily forms what?

Back 16

forms crosslinks
between DNA bases.

Front 17

Transplatin has a trans arrangement of chlorine atoms and that is the reason why transplatin is an ineffective what?

Back 17

an ineffective anticancer chemotherapeutic.

Front 18

Intrastrand cross-links most frequently occur between what?

Back 18

adjacent guanine residues referred to as diguanosinedinucleotides (60–65%) or adjacent guanine and adenine residues (25–30%).

Front 19

How often does intErstrand cross-linking occur compared to intrAstrand? What bases does intrEstrans involve?

Back 19

which occurs much less frequently (1–3%),usually involves guanine and adenine bases.

Front 20

Many of the antineoplastic antibiotic compounds inhibit what?

Back 20

topoisomerase II

Front 21

What is topoisomerase II?

Back 21

an enzyme responsible for maintaining proper DNA structure during replication and transcription to RNA.

Front 22

Topoisomerase II normally cleaves DNA during what phase?

Back 22

replication

Front 23

Topoisomerase II normally cleaves DNA during the replication phase but repairs its own what?

Back 23

damage after replication is complete

Front 24

Topoisomerase II inhibitors act to stimulate what? What do they inhibit? What does this leave?

Back 24

the cleavage reaction but inhibit the DNA resealing activity of the enzyme

leaving the DNA irreversibly damaged and unable to replicate.

Front 25

Yet another proposed mechanism of cytotoxic action is the generation of what? What does this cause?

Back 25

cytotoxic free radicals that cause single-strand breaks in DNA.

Front 26

One antibiotic _______ is capable of alkylating DNA

Back 26

mitomycin

Front 27

To bulldoze its way between the bonded DNA strands and cause a chemical change in DNA structure, a segment of the antibiotic must have what?

Back 27

the trigonal coplanar geometry guaranteed by aromaticity.

Front 28

Antibiotic antineoplastics that interact directly with DNA first intercalate what?

Back 28

the double-stranded helix

Front 29

Antibiotic antineoplastics that interact directly with DNA first intercalate the double-stranded helix by inserting between what?

Back 29

between the base pairs and forming strong noncovalent interactions with DNA bases

Front 30

Antibiotic antineoplastics that interact directly with DNA first intercalate the double-stranded helix by inserting between the base pairs and forming strong noncovalent interactions with DNA bases. The highly stabilized complex deforms what? What does this prohibit?

Back 30

deforms the DNA, prohibiting proper replication.

Front 31

Anthracycline antineoplastic antibiotics are very closely related to what?

Back 31

to the tetracycline antibacterials

Front 32

Anthracycline antineoplastic antibiotics are very closely related to the tetracycline antibacterials. Structurally, they are ____ and contain a ____ and a ____organic portion.

Back 32

glycosides

sugar portion

nonsugar

Front 33

Anthracycline antineoplastic antibiotics are very closely related to the tetracycline antibacterials. Structurally, they are glycosides and contain a sugar portion (L-daunosamine) and a nonsugar organic portion. The nonsugar portion of glycosides is generically referred to as an _____?

Back 33

aglycone

Front 34

In anthracyclines, the aglycone moiety is specifically called ____

Back 34

anthracyclinone or anthroquinone.

Front 35

Intercalation is most common in DNA regions that are rich in what?

Back 35

guanine and cytosine bases

Front 36

Antobiotics – Anthracyclines and Anthracenediones

The predominant cytotoxic effect is not due to the intercalation of this molecule in DNA, but the inhibition of _____?

Back 36

topoisomerase II

Front 37

. Anthracyclines bind to the DNA-enzyme complex in the area close to the DNA cleavage site. They stabilize what complex? What does this allow to happen to the DNA? What does it link to? What does it not permit?

Back 37

a ternary cleavable complex that allows the DNA to be cut and covalently linked to topoisomerase Tyr residues but that does not permit the cleaved DNA to reseal.

Front 38

The aromatic portion of the anthracyclinone ring system and the daunosamine sugar bind to _____


Where as anthracyclinone A ring is believed to bind with the ____ enzyme?

Back 38

DNA

topoisomerase II

Front 39

A very important mechanism of use-limiting anthracycline cardiotoxicity involves the formation of what?

Back 39

cytotoxic free radicals

Front 40

A very important mechanism of use-limiting anthracycline cardiotoxicity involves the formation of cytotoxic free radicals. NADPH/P450 reductase is the ____ for ____ enzymes

Back 40

electron donor protein for several oxygenaseenzymes

Front 41

When NADPH/CYP450 reductase reduces the quinone ring to a hydroquinone,___ ___ ___ are generated.

Back 41

superoxide radical anions

Front 42

Superoxide radical anions react to generate ___ ___? What does this reaction require? What is it catalyzed by?

Back 42

hydrogen peroxide, a reaction that requires protons and is catalyzed by the enzyme superoxide dismutase in a Cu2+mediated process.

Front 43

Anthracycline cardiotoxicity

In the presence of the enzyme catalase what happens to hydrogen peroxide?

Back 43

hydrogen peroxide is rapidly converted to water and oxygen.

Front 44

In the presence of ferrious Ion (Fe2+) what happens to hydrogen peroxide? What is this reaction known as?

Back 44

hydrogen peroxide is converted into the highly toxic hydroxyl radical through a process called the Fenton reaction.

Front 45

Hydroxyl radicals promote what in DNA? Why is this desireable?

Back 45

Hydroxyl radicals promote single-strand breaks in DNA, which is therapeutically desirable to treat the uncontrolled growth of cancer cells.

Front 46

Anthracyclineanti-cancer agents also are known to interfere with what?

Back 46

with normal ferritin-iron mobilization, resulting in iron accumulation

Front 47

The anthracyclines chelate strongly with what ions? What reduction is essentially guaranteed

Back 47

with di- and trivalent cations, including intracellularFe2+, so the generation of cytotoxic hydroxyl radicals after the initial NADPH/CYP450 reductase reduction is essentially guaranteed.

Front 48

____ ____ and ___ ___also are formed during the production of hydroxyl radicals

Back 48

Hydroxide anion and ferric ion (Fe3+)

Front 49

___ ___ is particularly vulnerable to free radical damage by the anthracyclines

Back 49

Cardiac tissue

Front 50

Cardiac tissue is particularly vulnerable to free radical damage by the anthracyclines because why?

Back 50

it does not contain the catalase enzyme.

Front 51

Cardiac tissue is particularly vulnerable to free radical damage by the anthracyclines because it does not contain the catalase enzyme. When hydrogen peroxide forms in the myocardium, which pathway is it forced to go down?

Back 51

Fenton Pathway

Front 52

Cardiac toxicity is the major use-limiting side effect of what?

Back 52

anthracycline use

Front 53

Cardiac toxicity is the major use-limiting side effect of anthracycline use, but coadministration of ______ has been shown to lower its incidence.

Back 53

dexrazoxane(anantioxidant and iron chelator)

Front 54

Additionally, the active form of anthracycline is a secondary alcohol which acts as an active what?

Back 54

cardiotoxic metabolite by disrupting the flow of myocardial cations.

Front 55

The active secondary alcohol metabolite formed by aldoketo reductase affects what? By increasing what? and inhibiting what?

Back 55

aldoketoreductase affects muscle tissue by increasing cytosolic levels of Ca2+ ions, and inhibiting Na,K–adenosine triphosphatase.

Front 56

The active secondary alcohol metabolite formed by aldoketoreductase affects muscle tissue by increasing cytosolic levels of Ca2+ ions, and inhibiting Na,K–adenosine triphosphatase. Collectively, these cellular events can induce a chronic ____?

Back 56

cardiomyopathy

Front 57

Chemically, mitoxantrone is classified as an ____?

Back 57

anthracenedione

Front 58

mitoxantrone has the structural features needed to do what?

Back 58

to intercalate DNA and inhibit topoisomerase II,

Front 59

This molecule has the structural features needed to intercalate DNA and inhibit topoisomerase II, but the enhanced stability of the quinone ring (possibly through an increased potential for intramolecular hydrogen bonding) makes the ring highly resistant to what?

Back 59

NADPH/CYP450 reductase.

Front 60

This molecule has the structural features needed to intercalate DNA and inhibit topoisomerase II, but the enhanced stability of the quinone ring (possibly through an increased potential for intramolecular hydrogen bonding) makes the ring highly resistant to NADPH/CYP450 reductase. This limits the formation of what?

Back 60

of the superoxide radicals that are required for the generation of the highly toxic hydroxyl radical.

Front 61

What structure is this?

Back 61

Mitoxantrone

Front 62

Mitomycin is used for what?

Back 62

Antibiotic for cancer chemotherapy

Front 63

Mitomycin is activated through what process?

Back 63

bioreductive process

Front 64

Mitomycin is activated through a bioreductive process utilizing what?

Back 64

NADPH/CYP450 reductase and/or NAD(P)H quinoneoxidoreductase 1 (NQ01 reductase), an enzyme expressed in many neoplastic cells.

Front 65

Mitomycin is activated through a bioreductive process utilizing NADPH/CYP450 reductase and/or NAD(P)H quinoneoxidoreductase 1 (NQ01 reductase), an enzyme expressed in many neoplastic cells. Through these enzymes, the quinone ring of mitomycin is reduced to what? What does this generate?

Back 65

to the hydroquinone, generating superoxide radicals in the process that ultimately will be converted to cytotoxic hydroxyl radicals through the Fenton reaction.

Front 66

Formation of the hydroquinone is followed by aromatization to the ___ ring, through the loss of ___?

Back 66

indole ring through the loss of methanol.

Front 67

Both the electrophilicaziridine ring and the methylene group adjacent to the carbamate ester are vulnerable to what? Such as what? What does this result in?

Back 67

to attack by DNA nucleophiles, such as the 2-NH2 group of guanine or the 4-NH2 group of cytosine, resulting in cross-linked DNA and cell death.

Front 68

What most commonly stop the de novo synthesis of DNA by inhibiting the formation of the nucleotides?

Back 68

antimetabolites

Front 69

The rate-limiting enzymes of nucleotide biosynthesis often are the primary target for what?

Back 69

antimetabolites

Front 70

Antimetabolites also are capable of inhibiting other enzymes required in what?

Back 70

the biosynthesis of DNA

Front 71

Antimetabolites also are capable of inhibiting other enzymes required in the biosynthesis of DNA and many can arrest __ ___ by promoting the incorporation of what?

Back 71

chain elongation by promoting the incorporation of false nucleotides into the growing DNA strand.

Front 72

The antimetabolites serve as false substrates for what enzymes?

Back 72

critical nucleotide biosynthesis enzymes

Front 73

Purine antagonists inhibit what?

Back 73

the synthesis of the purine-based nucleotides adenylatemonophosphate (AMP) and guanylatemonophosphate (GMP

Front 74

Pyrimidine antagonists stop the production of what?

Back 74

of the pyrimidine-based nucleotides, primarily deoxythymidinemonophosphate (dTMP)

Front 75

dTMP synthesis inhibitors inhibit what? What does this result in?

Back 75

inhibit thymidylate synthase either directly or indirectly, and this will result in a“thymineless death” in actively dividing cells.

Front 76

Without dTMP and its deoxythmidinetriphosphate metabolite what happens to the DNA?

Back 76

DNA will fragment, and the cell will die.

Front 77

Deoxythymdinemonophosphate (dTMP) is biosynthesized via what?

Back 77

C5-methylation of deoxyuridinemonophosphate (dUMP)

Front 78

The rate-limiting enzyme of the dTMP synthetic pathway is what?

Back 78

the sulfhydryl-containing thymidylatesynthase, with 5,10-methylene tetrahydrofolate(5,10-methylene-THF) serving as the methyl-donating cofactor.

Front 79

The breakdown of the ternary complex (enzyme-substrate-cofactor) yields ___ and ___

Back 79

a dTMP precursor and 7,8-dihydrofolate (DHF).

Front 80

The dTMP precursor rearranges to ____? What does this liberate?

Back 80

dtmp

liberating active thymidylate synthase enzyme, and the 7,8-DHF is converted back to the 5,10-methylene-THF cofactor

Front 81

active thymidylate synthase enzyme, and the 7,8-DHF is converted back to the 5,10-methylene-THF cofactor

Back 81

dihydrofolatereductase (DHFR) enzyme.

Front 82

Pyrimidine Antagonists - Direct Inhibitors of Thymidylate Synthase
Fluorouracil

To bind to thymidylate synthase, fluorouracil prodrug must be converted to what form?

Back 82

deoxyribonucleotide form

Front 83

The active form of fluorouracil differs from the endogenous substrate only by the presence of what? What is this the key too?

Back 83

the 5-fluoro group, which holds the key to the cell-killing action of this drug

Front 84

. The C6 position of the false substrate is significantly more ____ because why?

Back 84

electrophilic than normal because of the strong electron-withdrawing effect of the C5 fluorine.

Front 85

The C6 position of the false substrate is significantly more electrophilic than normal because of the strong electron-withdrawing effect of the C5 fluorine. This greatly increases the rate of attack by what?

Back 85

the cysteine of thymidylate synthase

Front 86

. The C6 position of the false substrate is significantly more electrophilic than normal because of the strong electron-withdrawing effect of the C5 fluorine. This greatly increases the rate of attack by the cysteine of thymidylatesynthase, resulting in a very fast formation of what?

Back 86

a fluorinated ternary complex

Front 87

Pyrimidine Antagonists - Direct Inhibitors of ThymidylateSynthase
Fluorouracil

The next step in the dTMP synthesis pathway requires the abstraction of what?

Back 87

C5proton by N10 of the cofactor, but this is no longer possible

Front 88

The next step in the dTMP synthesis pathway requires the abstraction of the C5proton by N10 of the cofactor, but this is no longer possible. Not only is the C5 fluorine bond stable to cleavage, the fluorine atom and N10 would repel one another because why?

Back 88

they are both electron rich

Front 89

The next step in the dTMP synthesis pathway requires the abstraction of the C5proton by N10 of the cofactor, but this is no longer possible. Not only is the C5 fluorine bond stable to cleavage, the fluorine atom and N10 would repel one another because they are both electron rich. The false ternary complex cannot do what? Is something formed? What is released? What is not regenerated?

Back 89

break down, no product is formed, nocofactor is released, and most importantly, the rate-limiting enzyme (thymidylatesynthase) is not regenerated

Front 90

Floxuridine prodrug is bioconverted via what? What is it converted to?

Back 90

via 2-deoxyuridine kinase–mediated phosphorylation to the same active 5-fluoro-dUMP structure generated in the multistep biotransformation of fluorouracil

Front 91

capecitabine is a carbamylated analogue of of what?

Back 91

cytidine

Front 92

Although capecitabine is a carbamylated analogue of cytidine, the drug actually is another ______ prodrug?

Back 92

5-fluoro-dUMP

Front 93

Although capecitabine is a carbamylated analogue of cytidine, the drug actually is another 5-fluoro-dUMP prodrug. Given orally, it is extensively metabolized to fluorouracil, which is then converted to what?

Back 93

to the active fluorinated deoxyribonucleotide

Front 94

Thymidine phosphorylase, an enzyme involved in this biotransformation, is much more active in ___ than ____? what does this improce?

Back 94

Thymidine phosphorylase, an enzyme involved in this biotransformation, is much moreactive in

Front 95

Levels of active drug in the tumor can be up to ____ than in surrounding tissue, leading to a lower incidence of side effects compared to fluorouracil therapy.

Back 95

3.5-fold higher

Front 96

What is methotrexate?

Back 96

Methotrexate is a folic acid antagonist structurally designed to compete successfully with 7,8-DHF for the DHFR enzyme.

Front 97

Methotrexate is a folic acid antagonist structurally designed to compete successfully with 7,8-DHF for the DHFR enzyme. The direct inhibition of DHFR causes what to build up? Which in turn results in what?

Back 97

cellular levels of 7,8-DHF to buildup, which in turn results in feedback (indirect) inhibition of thymidylatesynthase.

Front 98

The monoglutamate tail of methotrexate permits what?

Back 98

active transport into cells

Front 99

The monoglutamate tail of methotrexate permits active transport into cells. Once inside the cell, methotrexate undergoes what? What does this add?

Back 99

a polyglutamation reaction that adds several anionic carboxylategroups to trap the drug at the site of action

Front 100

The monoglutamate tail of methotrexate permits active transport into cells. Once inside the cell, methotrexateundergoes a polyglutamation reaction that adds several anionic carboxylategroups to trap the drug at the site of action. The C4 amino substituent of methotrexate enriches what?

Back 100

electron density at N1 through electron donation

Front 101

The monoglutamate tail of methotrexate permits active transport into cells. Once inside the cell, methotrexateundergoes a polyglutamation reaction that adds several anionic carboxylategroups to trap the drug at the site of action. The C4 amino substituent of methotrexate enriches electron density at N1 through electron donation, increasing its basic character between __ and ___ fold? What else does it promote?

Back 101

10- and 1,000-fold and promoting protonation at N1 by the key amino acid residue (Asp27) of DHFR.