Medicinal Chemistry : Test Ii : (Friehl)

Front 1

Most drugs are lipophilic or hydrophilic?

Back 1

Lipophilic

Front 2

How does the body ('bag of chemicals') get rid of foreign chemicals?

Back 2

Makes them water soluble

Front 3

What is a xenobiotic?

Back 3

exogenous chemical (ex. pesticide on food, lipstick, etc)

Front 4

During metabolism what is the difference between an enzyme and a co-enzyme?

Back 4

Enzymes do not change.

Coenzymes change (give or take).

Front 5

Are enzymes always reqd during metabolism?

Back 5

no

Front 6

What are the sources of elimination from the body for a xenobiotic or lipophilic drug after it metabolizes into metabolites?

Back 6

1. URINE (Main source of elim)

2. bile

3. sweat

4. saliva

5. lungs

6. milk

Front 7

What 3 general things does drug metabolism lead to?

Back 7

1. Termination of drug action

2. Bioactivation of drug

3. Drug intrxns

Front 8

In what 3 ways might a drug action be terminated?

Back 8

1. Bioinactivation

2. Detoxification

3. Elimination

Front 9

In what 2 ways might a drug be bioactivated?

Back 9

1. Prodrugs (inactive until metabolized)

2. Active metabolites (some drugs are active with active metabolites...ex) longer t1/2...different drug-drug intrxns)

Front 10

What is the most important site for drug metabolism?

Back 10

Liver

Front 11

List 8 sites of drug metabolism?

Back 11

1. LIVER

2. intestine

3. kidney

4. lung

5. adrenal glands

6. brain

7. skin

8. placenta and fetus

Front 12

How might the intestine be involved in drug metabolism?

Back 12

1. Digestive secretions (esterases, lipases, etc)

2. Intestinal wall (ex. sulfotransferases)

3. Bacterial flora in the intestine have their own enzymes (ex. reductase)

Front 13

All sites of drug metabolism contain what?

Back 13

enzymes

Front 14

A polar molecule is hydrophilic or hydrophobic?

Back 14

Hydrophilic

Front 15

Explain a situation that might occur between a drug and a placent/fetus?

Back 15

Most drugs can pass through the placenta because they are lipophilic.

Once through they may become a hydrophilic metabolite that can't leave and could build up to toxic concentrations.

Front 16

Phase I rxns are aka what?

Back 16

Functionalization rxns

Front 17

Phase I (Functionalization rxns) could be referred to as "? rxns".

Back 17

"little rxns"...putting a little group on or off

Front 18

List 3 phase I rxns?

Back 18

1. Oxidative rxns

2. Reductive rxns

3. Hydrolytic rxns

Front 19

Phase II rxns could be referred to as "? rxns".

Back 19

Big rxns...putting something big and H2O soluble on molecule to help excrete it.

Front 20

List 5 types of Phase II rxns?

Back 20

1. Glucuronic acid conjugation

2. Sulfate conjugation

3. Glycine, glutamine and AA conjugations

4. Acetylation

5. Methylation

Front 21

Do drugs undergo only phase I or phase II rxns but not both?

Back 21

Drugs may undergo Phase I, Phase II, or both.

MOST drugs undergo BOTH.

Front 22

Covalent bonds share electrons in what way?

Back 22

Equally

Front 23

What does arrow pushing show?

Back 23

The movement of only electrons

Front 24

What is the purpose of a Phase I rxn?

Back 24

To make a compound more polar to ultimately enhance excretion.

1. Enhance excretion (more h2o soluble)

2. Prepare for phase II rxns (add functional group "handle")

Front 25

How might a phase I rxn make a compound more excretable?

Back 25

Add a hydroxyl group (more water soluble)

Front 26

Why would you add a 'handle' to a compound through a phase I rxn?

Back 26

Because Phase II rxns require a handle to attach their 'big group' to.

Front 27

What is the most common phase I rxn?

Back 27

oxidative biotransformations

(oxidation)

Front 28

What enzyme systems carry out oxidative biotransformations (oxidation)?

Back 28

Mixed Function Oxidases, Monoxygenases, or Cyp450.

Front 29

A mixed function oxidase system involves what enzyme?

Back 29

Cytochrome P450

Front 30

What are the two parts of a mixed function oxidase system (P450)

Back 30

1. Apoprotein

2. Protoporphyrin

Front 31

What does the apoprotein part of an MFO bind to?

Back 31

part that binds to drug

Front 32

What does the protoporphyrin part of an MFO bind to?

Back 32

It has the heme part, has iron, binds Oxygen

Front 33

Are apoproteins or protoporhyrins responsible for the variety of cyps observed?

Back 33

apoprotein (aa sequence)

Front 34

Why are drugs specific to different binding sites?

Back 34

Because of different AA sequences...most variable being at the substrate binding site.

Front 35

Where is cytochrome P-450 found?

Back 35

1. LIVER (high concentrations)

2. kidney

3. intestine

4. skin

5. placenta

6. adrenal cortex

Front 36

Why could cytochrome P-450 be called a versatile enzme?

Back 36

It is capable of oxidizing many substrates. This may be due to the multiple forms of the enzyme. The apoprotein portion vary in their tertiary structure. This may account for differences in substrate binding.

Front 37

Describe a reduction?

Back 37

Rxn that effects a molecule by:

Increases hydrogen content

OR

Decreases Oxygen, Nitrogen, Halogen content

Front 38

Describe an oxidation?

Back 38

Rxn that effects a molecule by:

Decreasing the hydrogen content

OR

Increasing the oxygen, nitrogen, or halogen

Front 39

Why would the oxidation of aromatic moieties be a huge part of drug metabolism?

Back 39

Because most drugs have aromatic (phenyl) rings...only one point of substitution.

Front 40

For monosubstituted benzene rings hydroxylation occurs at what position?

Back 40

Para(primarily...but can also be ortho or meta)

Front 41

Most phenolic metabolites undergo what?

Back 41

Further phase II rxns (remember oxidation is phase I...gives handle for phase II)

Front 42

Hydroxylation of a compound does what to it?

Back 42

oxidizes it

Front 43

Substituents on an aromatic ring may influence the ease of hydroxylation.

Aromatic hydroxylation rxns proceed most readily in ? rings.

Back 43

Hydroxylation rxns proceed most readily in activated (electron rich) rings.

Front 44

Which aromatic rings are slow or resistant to hydroxylation?

Back 44

Those containing electron withdrawing groups. (deactivated)

Front 45

List 4 electron withdrawing groups?

Back 45

1. Cl

2. -N+R3

3. COOH

4. SO2NHR

Front 46

For compounds with 2 aromatic rings what occurs with hydroxylation?

Back 46

Usually only at on ring.

An example would be phenytoin.

Usually occurs preferentially in the more electron-rich ring...so in a ring with e-donors or without e-withdrawers.

Front 47

What is an arene oxide?

Back 47

unstable electrophilic compound.

intermediat formed during oxidation of aromatic rings

Front 48

Arene oxides are ? and ? ?.

Back 48

Electrophilic and Chemically reactive.

(electron loving so it has a positive charge)

Front 49

Arenes can undergo what 3 COMPETING rxns?

Back 49

1. Formation of arenols

2. Formation of trans-dihydrols

3. Formationn of glutathione adducts (phase II)

(also may react with nucleophilic functional groups on DNA, RNA, and other macromolecules. Can cause toxicity)

Front 50

An arenol is a ? product of an arene oxide.

Back 50

Hydroxylated product (OH)

Front 51

The formation of trans-dihydrodiols from an arene oxide requires what enzyme?

Back 51

Epoxide hydrolase

Front 52

A glutathione adduct is formed from an arene oxide via what enzyme?

Back 52

Glutathione S-transferase (transfers glutathione via sulfur)

Front 53

The formation of a glutathione adduct is a detoxification pathway for what?

Back 53

For electrophiles (changes them to nucleophile?)

Front 54

Most drugs are nucleophiles or electrophiles?

Back 54

Nucleophiles

Front 55

What macromolecule adducts may be involved with arene oxide rxns?

Back 55

DNA, RNA, proteins.

Front 56

What is a NIH shift?

Back 56

Phase I

Rearrangement of an arene oxide to an arenol.

Front 57

NIH shifts occur with ? as well as with ?.

Back 57

With substituents as well as with hydrogen.

Front 58

Primary alcohols are often further oxidized to ? and ? ?.

Back 58

Often further oxidized to aldehydes and carboxylic acids.

Front 59

What is a benzylic carbon?

Back 59

C on benzene ring

Front 60

Alkyl side chains are often metabolized on the ? or ? carbon.

Back 60

Terminal or Penultimate carbon.

Front 61

The 2 types of side chain oxidations?

Back 61

1. w (omega)

2. w-1 (omega minus 1)

Front 62

Which carbon is the penultimate carbon?

Back 62

The next to last C in a chain.
(w-1)

Front 63

Pentobarbital undergoes what kind of side chain oxidation?

Back 63

w-1 (penultimate)

Front 64

Secobarbital undergoes what kind of side chain oxidation?

Back 64

w (terminal)

Front 65

Cyclohexane rings have no ? bonds.

Back 65

No double bonds...(chair)

Front 66

Cyclohexane rings usually undergo what kind of oxidations?

Back 66

3-hydroxylation or 4-hydroxylation

(on C3 or C4)

Either one would give both a cis and a trans product

Front 67

Concerning cyclohexane ring oxidation acetohexamide is metabolized to what?

Back 67

The trans 4-hydroxyacetohexamide.

Front 68

Alkene hydroxylation leads to what?

Back 68

Epoxide formation

Front 69

Alkene epoxides are more or less stable than arene oxides?

Back 69

More stable.

Front 70

Like arene epoxides alkene hydroxylation products (epoxides) are susceptible to what?

Back 70

Enzymatic hydration by epoxide hydrolase to form 1,2 dihydrodiols...also GSH transferase rxns.

Front 71

What is N-oxidation?

Back 71

Direct oxidation on a Nitrogen atom.

Front 72

N-oxidation usually occurs with what?

Back 72

Secondary or tertiary amines.

(and primary aromatic rings)

Front 73

What is N-dealkylation?

Back 73

Removes N substituents such as methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, benzyl and other having an alpha-proton.

Usually occurs on the smaller alkyl group first.

Front 74

Tertiary amines are dealkylated to secondary amines faster than what?

Back 74

Faster than secondary amines are dealkylated to primary amines.

Front 75

During N-dealkylation, oxidation occurs on which carbon?

Back 75

The carbon alpha to (next to) the nitrogen.

Front 76

Nitrogen wants how many bonds?

Back 76

3

Front 77

Nitrogen with 2 bonds has what charge?

Back 77

negative

Front 78

Nitrogen with 4 bonds has what charge?

Back 78

positive

Front 79

So N-dealkylation subtracts a what?

Back 79

alkyl group

Front 80

What is deamination?

Back 80

Removing nitrogen from drugs...same mxm as n-dealkylation.

Front 81

In deamination oxidation occurs on which carbon?

Back 81

Carbon alpha to (next to) the nitrogen.

Front 82

Deamination requires alpha carbon ? first, forming the ?, followed by ?.

Back 82

Requires alpha carbon oxidation first, forming the carbinolamine, followed by CN cleavage.

Front 83

Propanolol has how many alpha carbons?

Back 83

2

Front 84

What is O-dealkylation?

Back 84

Similar mxm as N-dealkylation.

Hydroxylation on the carbon attached to the oxygen followed by C-O cleavage to give the alcohol and the aldehyde or ketone.

Front 85

People allergic to morphine can't take codeine for what reason?

Back 85

Because it converts to morphine via O-dealkylation.

If you are missing the O-demethylase enzyme than you won't be allergic but it won't be effective anyway.

Front 86

List 3 phase I rxns that involve the oxidation of carbon-sulfur systems.

Back 86

1. Oxidative S-dealkylation

2. Desulfuration

3. S-oxidation

Front 87

What is S-dealkylation?

Back 87

The removal of the aklyl group from the sulfur

Front 88

What is a desulfuration rxn?

Back 88

Conversion of C=S to C=O

Front 89

What is S-oxidation catalyzed by?

Back 89

Catalyzed by flavin monooxygenase and CYP450

Front 90

What is a chiral center?

Back 90

C...4 different substituents

Front 91

Can a carbon with a dbl bd be chiral?

Back 91

NO

Front 92

What does the prefix azo- refer to?

Back 92

nitrogen

Front 93

Where are esterases found in the body?

Back 93

"everywhere"...a lot of drugs have esters in them

Front 94

What are the two most important rxns in this course?

Back 94

1. Ester hydrolysis

2. Amides Hydrolysis

Front 95

What enzyme is responsible for ester hydrolysis?

Back 95

esterase

Front 96

What enzyme is available for amide hydrolysis?

Back 96

amidase

Front 97

Esters hydrolyzed by esterases produce what kind of products?

Back 97

1. Carboxylic acids

2. Alcohols

3. Phenols

Front 98

Amides hydrolyzed by amidases produce what kind of products?

Back 98

amines

Front 99

If a carbon atom is partially positive what does it mean?

Back 99

It is an electrophile. It means the e-s are pulled away from the molecule toward surrounding molecules (like Oxygen).

It will be seeked out by nucleophile.

Front 100

What does an enzyme do to a rxn?

Back 100

speeds it up (the rxn would occur with or without it)

Front 101

Carbon desires how many bonds?

Back 101

4

Front 102

Oxygen desires how many bonds?

Back 102

2 (or one and 2 e-s)

-O:

Front 103

Electrophiles get ?, they never do what.

Back 103

Electrophiles get attacked they never do the attacking (remember during arrow pushing)

Front 104

Where is a bad place to store an ester med. Why?

Back 104

Warm, damp places. Because it gives them hydrogen to react with.

(ex. ASA)

Front 105

Water is a strong what?

Back 105

nucleophile

Front 106

Is an ester or amide more stable?

Back 106

amides are more stable (undergo hydrolysis less frequently). longer t1/2.

Front 107

Nitrogen is electron ?.

Back 107

donating

Front 108

Phase II rxns could also be referred to as what?

Back 108

Conjugation rxns (big rxns)

Front 109

Phase II rxns are essentially doing what to a drug?

Back 109

"Puts a big H20-soluble compound on drugs"

Front 110

Phase II rxns act on what?

Back 110

Parent drug or phase I metabolite

Front 111

Can a phase II occur without a phase I?

Back 111

yes, as long as there is a chemical handle on the compound

Front 112

What is the most common Phase II rxn in an adult's body?

Back 112

Glucoronidation.

Used to get rid of drugs.

Front 113

Where is there lots of glucoronic acid available?

Back 113

In the liver.

Front 114

What is the glucorinadation rxn?

Back 114

Rxn is the direct condensation of the drug with the active form of glucoronic acid (uridine diphosphate glucuronic acid)(UDPGA)(a coenzyme)

Front 115

List 6 'handles'. The reqt for a phase II rxn?

Back 115

1. -OH

2. -COOH

3. -NH2

4. -NR2

5. -SH

6. C-H

Front 116

Glucoronidation transfers what to a drug?

Back 116

Glucoronic acid

Front 117

Glucorination is an SN1 or SN2 rxn?

Back 117

SN2

Front 118

What does glucorinadation cause a molecules configuration to do?

Back 118

Causes inversion.

alpha link to beta link

Front 119

Will an oxygen on a ring break during glucorindation?

Back 119

no

Front 120

What kind of rxn is a sulfate conjugation?

Back 120

A phase II rxn.

Front 121

List some functional groups that undergo sulfate conjugation.

Back 121

1. Alcohols

2. arylamines

3. N-hydroxy compounds

4. PHENOLS (primary one)

Front 122

Often sulfate conjugation and what can occur on the same substrate?

Back 122

glucoronidation

Front 123

Where is the only place where sulfate conjugation predominates?

Back 123

phenol hydroxyls

AND

IN CHILDREN (vs. glucorinidation in adults)

Front 124

What enzyme is involved in sulfate conjugation?

Back 124

Sulfotransferase

Front 125

What is the co-enzyme involved in sulfate conjugation?

Back 125

3' phosphoadenosine-5' phosphosulfate (PAPS)(limited supply)

Front 126

Unlike glucorinidation, sulfate conjugation has a what?

Back 126

Intermediate

Front 127

For albuterol deamination to occur what must be present?

Back 127

Alpha C next to N with an alpha proton

Front 128

What is reqd for glucorinidation?

Back 128

-OH

Front 129

What kind of rxn is AA conjugation?

Back 129

Phase II

Front 130

AA conjugation of CARBOXYLIC ACIDS leads to what?

Back 130

Amide bond formation

Front 131

What AAs can be added to a drug?

Back 131

almost any of them

1. GLYCINE (smallest and most abundant)(predominates)

2. glutamine, arginine, asparaginine, histidine, lysine, glutamate, aspartate, alanine and serine.

Front 132

What is absolutely reqd as a handle for AA conjugation?

Back 132

Carboxylic acids (COOH)

Front 133

For an AA conjugation to occur what must happen first? Where can this occur?

Back 133

The drug must first get activated by ATP and Coenzyme A (CoA) to form an acyl-CoA complex.

The rxn occurs in the mitochondria of liver and kidney cells.

Front 134

AA acids conjugations req 2 seperate what?

Back 134

2 seperate enzymes and co-enzymes

Front 135

The AA acid is always attached by it's what?

Back 135

Nitrogen

Front 136

AA conjugation is a ? rxn.

Back 136

Detoxifying (COOH is reqd so molecule is already water soluble)

Front 137

If there is no COOH on a molecule than what is reqd for an AA conjugation?

Back 137

Phase I rxn first

Front 138

What is the nucleophile in AA conjugation?

Back 138

nitrogen of AA

Front 139

List two phase I rxns that could give a COOH to a molecule so it could undergo AA conjugation?

Back 139

1. Deamination

2. Oxidation

Front 140

What enzyme is reqd for the co-enzyme glycine in AA conjugation rxn?

Back 140

Glycine N-acyltransferase

Front 141

Does acetylation make things more water soluble?

Back 141

No...just detoxifies

Front 142

N-acetylation is what type of rxn?

Back 142

Phase II

Front 143

What does N-acetylation rxn put on a molecule?

Back 143

Puts acetyl group on a nitrogen.

Front 144

In N-acetylation what kind of group is converted?

Back 144

PRIMARY amine

Front 145

IN N-acetylation a primary amine is converted to what?

Back 145

Converted to an UNCHARGED amide...which is less soluble (but detoxified)

Front 146

The extent of N-acetylation is dependent upon what?

Back 146

Genetically determined.

Three phenotypes:

1. Homozygous fast

2. Homozygous slow

3. Heterozygous (intermediate) acetylators

Front 147

What does glutathione conjugation break down to?

Back 147

Mercapturic acid (synthesizes it)

Front 148

Describe glutathione conjugation and mercapturic acid synthesis?

Back 148

1. ELECTROPHILIC drugs/xenobiotics react with GSH to form S-substituted GSH adducts.

2. GSH is a tripeptide (lamda-glutamyl-cysteinyl-glycine) (cysteine has the sulfur...the nucleophile to attack the electrophile drug)

3. Usually not eliminated, undergoes further transformation to N-acetylcysteine products called mercapturic acids...less toxic compounds.

Front 149

Electrophilic drugs can be very what? Why?

Back 149

Toxic. Because they can be attacked by nucleophile DNA and proteins.

Front 150

What happens to mercapturic acid?

Back 150

eliminated in urine

Front 151

Drug is the ?phile...GSH is the ?phile.

Back 151

Drug = electrophile

GSH = nucleophile

Front 152

Methylation is what type of rxn?

Back 152

Phase II

Front 153

Are methyl groups polar?

Back 153

no

Front 154

What does methylation put on a molecule?

Back 154

-CH3

Front 155

What is the major role of methylation?

Back 155

Major role is in the biosynthesis of endogenous compounds-more polar compounds?

Front 156

What is O-methylation?

Back 156

methyl on oxygen

Front 157

What is O-methylation catalyzed by?

Back 157

Methyltransferases

Front 158

What is COMT?

Back 158

Catechol-O-methlytransferase

O-methylation specific for catechol metabolism.

extremely important enzyme

Front 159

What is N-methylation?

Back 159

Methyl on nitrogen

Methylation of primary and secondary amines.

Front 160

What is S-methylation?

Back 160

Methyl on sulfur

Thiols are generally toxic...this detoxifies them