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Medicinal Chemistry > James Medchem Lecture 2 (Powerpoint 2) > Flashcards

James Medchem Lecture 2 (Powerpoint 2) Flashcards

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1
Q

In phase 2 reactions, a functional group in the drug combines with a…

A

“small, usually water-soluble, endogenous molecule (co-substrate)”

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2
Q

The product of most (not all) phase 2 reactions is _______ at physiological pH

A

anionic

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3
Q

Most phase 2 metabolites are either excreted into _____ by a combination of glomelular filtration or into _______ by active transport

A

Urine; bile

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4
Q

What are the 5 important phase 2 reactions?

A 
Glucuronide conjugation
Sulfonation
Glutathione conjugation
Acetylation
Amino acid conjugation
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5
Q

Glucuronide conjugation is catalyzed by which enzyme

A

UDP-glucuronosyltransferases, or UGT

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6
Q

What co-substrate is required for glucuronide

A

UDP-glucuronic acid

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7
Q

True or False: Most glucuronides are not biologically active

A

True

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8
Q

Glucuronides are anions at what pH?

A

7.4

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9
Q

To what atoms can UGT add UDP-glucuronic acid to? AKA RXH - what X’s?

A

O, N, S, or acidic C

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10
Q

What group of glucuronic acid is anionic at pH 7.4, facilitating excretion?

A

Carboxyl group (COO-)

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11
Q

Where is there an inversion of configuration during glucuronidation reactions?

A

At the glucuronic acid carbon, where the RX group adds

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12
Q

Acyl glucuronides (carbon group + carboxyl group at the end reacting with UGT) are chemically reactive. Further reaction of these metabolites may lead to the drug being ___________. This may trigger __________.

A

Bound to proteins; an immune response

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13
Q

What functional groups can undergo sulfate conjugation?

A

Alcohols, phenols, and amines

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14
Q

Why don’t carboxylic acid groups form sulfate conjugates?

A

It is an unstable product

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15
Q

What enzyme catalyzes sulfonation?

A

PAPS-sulfotransferase enzyme family, or SULT

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16
Q

What co-substrate is required for sulfonation?

A

3’-phosphoadenosine-5’-phosphosulfate (PAPS)

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17
Q

What is the final product of a sulfonation reaction?

A

RXH + PAPS = RX-sulfonic acid group

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18
Q

At a low dose of drug, which is most likely to occur: Sulfonation or Glucuronidation?

A

Sulfonation

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19
Q

At a high dose of drug, which is most likely to occur: Sulfonation or Glucuronidation?

A

Glucuronidation

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20
Q

What enzyme catalyzes glutathione conjugation?

A

Glutathione-transferases, or GST

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21
Q

What co-substrate is required for glutathione conjugation?

A

γ-glutamyl-cysteinyl-glycine, aka glutathione (abbreviated GSH)

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22
Q

________ groups in drugs form glutathione conjugates

A

Electrophilic

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23
Q

What are some examples of electrophilic groups?

A

Alkyl halides, some aryl halides, α,β-unsaturated ketone, and epoxides

24
Q

Electrophilic groups are only found on drugs that are used to…

A

Kill cells, such as cancer cells

25
Q

The product of glutathione conjugation is not secreted as such. It is further metabolized in several steps to the final metabolite, ___________.

A

N-acetyl-cysteine conjugate. Also known as mercapturic acid

26
Q

GSH conjugation is very often a _________ reaction, as it protects the cell from damage caused by ________.

A

Detoxification; electrophiles

27
Q

What reaction detoxifies the reactive metabolite produced by a minor pathway of acetaminophen?

A

GSH conjugation

28
Q

What enzyme catalyzes acetylation?

A

N-acetyl-transferases, abbreviated NAT

29
Q

What co-substrate is needed for acetylation?

A

Acetyl-coenzyme A

30
Q

What was the enzyme listed that first showed genetic polymorphism in people?

A

NAT enzymes (NAT-2)

31
Q

Which metabolite given in the powerpoint is the only one that is not anionic after the phase 2 reaction?

A

Acetylated metabolites

32
Q

Describe the discovery of amino acid conjugates

A

Benzoic acid was fed to horses and a white crystalline substance was isolated from the horse urine. The substance was known to be an acid, and was named “hippuric acid” (hippos = horse). The substance was shown to be benzoylglycine.

33
Q

What are the substrates of amino acid conjugation? (what is reacted with)

A

Carboxylic acids

34
Q

What are the two steps in amino acid conjugation?

A

Formation of a coenzyme A intermediate (replace the OH of a carboxyl group with S-CoenzymeA)
Formation of the conjugate (replace the S-CoenzymeA with glycine, which is N-CH2-COOH)

35
Q

What enzymes catalyze the two steps of amino acid conjugation?

A

First: acyl-coenzyme A ligase
Second: acyl-coA-amino acid N-acyltransferase

36
Q

What conjugates are very good substrates for transporters?

A

Amino acid conjugates

37
Q

What are the relative percentages of each phase 2 reaction?

A 
UGT's 45%
SULTs 20%
GSTs 15%
NATs 5%
Amino acid conjugation 5%
38
Q

What are the minor phase 2 reactions? Why are they different?

A

Methylation, Fatty acid conjugation, Cholesterol ester formation
They don’t increase the water solubility

39
Q

Drugs with the ____________ group are common substrates for Methylation reaction

A

Catechol (two alcohols on an aromatic ring)

40
Q

What enzymes catalyze methylation?

A

S-adenosine-methyl transferase

41
Q

What co-substrate is necessary for methylation?

A

S-adenosylmethionine (SAM)

42
Q

What enzyme catalyzes the O-methylation of a catechol group?

A

Catechol O-methyltransferase

43
Q

Why isn’t esterification with endogenous fatty acids/alcohols easy to follow?

A

Because the products are more fat soluble so they are stored in fatty tissue

44
Q

Which minor phase 2 reaction may contribute to prolonged duration of action of some drugs?

A

Esterification with endogenous fatty acids or alcohols

45
Q

What happens during fatty acid conjugation?

A

The carboxylic acid goes from COOH to COO-CH2-CH2-Cl-

46
Q

What enzyme is used to catalyze cholesterol ester formation?

A

Ester hydrolase

47
Q

What enzyme is used to catalyze fatty acid conjugation?

A

Ester hydrolase

48
Q

What are Phase III reactions?

A

The process of transporter protein-aided removal of drugs and drug metabolites out of the cell “phase III” pathways

49
Q

What are SLC’s?

A

Solute carrier proteins
They are involved in uptake AND efflux
No ATP required

50
Q

What are ABC’s?

A

ATP binding cassette protein
Only involved in efflux
ATP required

51
Q

Why are ABC’s related to resistance of anti-cancer drugs?

A

Cancer cells start overproducing efflux protein, and pumps out the anti-cancer drug, preventing it from killing the tumor cell

52
Q

What is MDR1?

A

Multi-Drug Resistance protein 1 aka p-glycoprotein

Transport protein that can take neutral or weakly cationic drugs and efflux them out of the cell, with energy from ATP

53
Q

Some anionic metabolites can be effluxed from cells with the aid of…

A

MRP2

54
Q

What are OATs?

A

A family of SLC’s

55
Q

OAT1 transporter is found in kidney tubules, where it facilitates uptake of _______ from the blood into the kidney tubule.

A

Glycine conjugates

Medicinal Chemistry (6 decks)

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