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444 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Review Questions
1. Chiral carbon atoms are identified below with asterisks. Circled carbon atoms are identified
below as being prochiral or not prochiral.
2. The R enantiomer is drawn. This is based on the following priorities:
Priority #1: Aromatic heterocycle (pyridine)
Priority #2: CH2-to geminally substituted cyclopentane
Priority #3: CH2CH2-O
Priority #4: CH2CH2-NH
3. Similar properties: molecular weight, infrared (IR) and nuclear magnetic resonance (NMR)
spectral properties, log P values, water/lipid solubility balance, dissolution rates, pKa values
of any acidic or basic functional group, and the percent ionization of these functional groups
at any given pH value.
Different property: direction that the molecule rotates plane polarized light. /
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 445
d/l
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4. Correct matches are shown below.
(+)/(−) matches with Direction that enantiomer rotates plane polarized light
Dextrorotatory/levorotatory
d/l matches with Direction that enantiomer rotates plane polarized light
Dextrorotatory/levorotatory
matches with Absolute configuration
Steric arrangement of atoms about a chiral carbon
R/S matches with Absolute configuration
Steric arrangement of atoms about a chiral carbon
5. Part A: Only one (+)/(−) designation that indicates the net rotation of plane polarized light.
Part B: Yes, it can have an enantiomer (nonsuperimposable mirror image), a diastereomer
(nonsuperimposable nonmirror image), and conformational isomers (nonsuperimposable
isomers that differ due to free rotation of atoms about single bonds). There is not enough
information provided to determine if a geometric isomer is possible (e.g., no information
related to presence of rings or double bonds).
6. Sotalol is sold as a racemate. It is possible that the two biological targets (potassium chan-
nel and β receptor) have stereochemical differences for their interaction requirements. As
an example, let’s assume that when the R enantiomer interacts with the β receptor, the
hydroxyl group is oriented in a direction that allows it to participate in a required ion–dipole
interaction with a charged functional group located within the biological target. In the S
enantiomer, this hydroxyl group is oriented in the opposite direction of the R enantiomer
and is not able to participate in the required ion–dipole interaction with the biological target. At the potassium channel, the binding requirements for this same hydroxyl group are
different, thus allowing the S enantiomer to participate in a key hydrogen bond but not the
R enantiomer.
7. Chiral carbons are circled. Prochiral carbons are boxed.
Fenfluramine is available as a mixture of D/L isomers; however, the -isomer causes signifi-
cant drowsiness. The -isomer has a methyl group pointed behind the plane of the paper,
whereas the -isomer has a methyl group pointed in front of the plane of the paper. Since
drowsiness is associated with the -isomer, one might guess that this methyl group is
important in activating the biological target that causes drowsiness (or prevents alertness).
446 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
8. Chiral centers have been circled below.
Similarities to enantiomers: Same molecular formula, not superimposable
Differences from enantiomers: Not mirror images, different chemical and physical
properties, may have different pharmacological activities
At least one of the stereocenters has not changed configuration between the two struc-
tures; therefore, these two isomers are diastereomers.
9. Priority of the double bond substituents using the CIP system are listed below.
Priority #1: Aromatic ring directly attached to the ether oxygen atom
Priority #2: Aromatic ring attached to methylene carbon then to ether
Priority #1′: Ethyl chain attached to tertiary amine
Priority #2′: Hydrogen atom
oxygen atom
10. Part A: Chiral centers are highlighted with an asterisk. The carbon atom circled on the
structure of nifedipine is not chiral since the ring is symmetrical at that carbon atom.
Part B: Acebutolol, estradiol, and cefamandole can have enantiomers, while nifedipine can-
not. For a drug molecule to have an enantiomer, its structure must contain at least one
chiral center. Acebutolol, estradiol, and cefamandole all meet this criterion. Because the
structure of nifedipine does not contain a chiral center, it cannot have enantiomers.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 447
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Part C: Estradiol and cefamandole can have diastereomers, while acebutolol and nifedipine
cannot. For a drug molecule to have a diastereomer, its structure must contain at least
two chiral centers. Because the structures of estradiol and cefamandole have five and three
chiral centers, respectively, these two drug molecules meet this criterion and can have diastereomers. Acebutolol (one chiral center) and nifedipine (0 chiral centers) do not meet
this criterion and thus cannot have diastereomers.
Part D: Estradiol and cefamandole can have geometric isomers, while acebutolol and
nifedipine cannot. Geometric isomers are a specialized type of diastereomer and result
from the restricted rotation about a carbon-carbon bond. Geometric isomers can occur due
to the presence of either a double bond or an alicyclic ring. Both estradiol and cefamandole
contain alicyclic rings and thus can have geometric isomers. Acebutolol and nifedipine do
not meet the above criteria and thus cannot have geometric isomers. Please note that the
double bonds seen in the 1,4-dihydropyridine ring of nifedipine reside in a six-membered
ring and thus cannot participate in the formation of geometric isomers.
Enantiomers have identical physical and chemical properties, with the exception of the
11.
direction in which they rotate plane polarized light. Thus, water solubility and the percent
ionization of the carboxylic acid at a pH of 7.4 would be expected to be identical. The major
difference, and most important aspect of enantiomers, is their relative abilities to interact
with three dimensional biological targets. Hepatic metabolism and active renal reabsorption depend on binding to metabolizing enzymes and transport proteins, respectively, and
would be expected to be different. Adverse effects can be due to the interaction of these
drug molecules with other biological targets and/or the formation of a specific metabolite.
Differences in potency can result in differential metabolism (i.e., one enantiomer may be
inactivated quicker than the other) or differential binding to the biological target.
12. For the purposes of this question, each bond has been rotated by 180°. Other rotations are
also possible.
Rotation about bond A alters the orientation of the ethyl chain, such that the terminal
carbon atom is now further away from the nitrogen atom of the pyridine ring. If the binding
site for this ethyl chain matched this orientation (shown in the figure below), then this conformational isomer should demonstrate enhanced binding. On the other hand, if the binding site did not match this orientation, then this conformational change would decrease
the interaction of pioglitazone with its receptor.
Rotation about bond B alters the orientation of the para-ethyl pyridine ring relative to the
thiazolidinedione ring. If the binding sites of the para-ethyl pyridine ring and the thiazolidinedione ring matched this orientation (shown in figure below), then this conformational
isomer should demonstrate enhanced binding. As with the first example, if the binding sites
448 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
did not match this orientation, then this conformational change would decrease the binding of pioglitazone to its receptor.
Rotation about bond C alters the orientation of the acidic thiazolidinedione ring relative
to the rest of the molecule. Since ionic interactions often play a key role in the binding of
a drug to its biological target, it is important that ionizable functional groups are correctly
orientated to form these bonds. If the binding site for pioglitazone matches the orientation
shown below, then this conformational isomer should demonstrate enhanced binding. If
this orientation did not match the binding site of pioglitazone, then this conformational
change would participate in fewer interactions.
CHAPTER 8
Structural Analysis Checkpoint
Checkpoint Drug 1: Venetoclax
1. Shown below is the answer provided in Chapter 7. Of the 14 potential prochiral centers,
only four of these (1-4) are valid. Carbon atoms 1 and 4 are allylic carbon atoms and can
undergo allylic oxidation that would make these carbon atoms chiral. Either one of the
methyl groups attached to carbon atom 2 can undergo ω oxidation, thus making carbon
atom 2 chiral. Alicyclic rings can be oxidized at C3 and C4 positions. Carbon atom 3 resides
at either the C3 position relative to carbon atom 5 or the C4 position relative to the para-
chlorophenyl ring. Oxidation of this carbon atom would create a chiral center; however,
the probability of this metabolic transformation is decreased due to steric hindrance by
the adjacent dimethyl substitution. Oxidation at carbon atoms 5 to 10 can occur during
the process of oxidative N-dealkylation. While the initial oxidation of these carbon atoms
produces a chiral center, the resulting carbinolamine is unstable and readily forms an
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 449
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aldehyde. The same is true with carbon atoms 12 and 14 as they can be involved with oxidative O-dealkylation. Oxidation at carbon atoms 11 and 13 is highly unlikely. As mentioned
above, alicyclic rings can be oxidized, but this normally occurs at the C3 and C4 positions of
a cyclohexane ring and not at the carbon atoms adjacent to the aliphatic chain.
2. Metabolic Pathway A: No. Benzylic oxidation is a Phase I metabolic transformation that
requires an aliphatic carbon atom that is directly attached to an aromatic ring. While
the structure of venetoclax contains four aromatic rings, only two of these are directly
attached to an aliphatic carbon. Neither of these aliphatic carbon atoms have a hydrogen
atom attached and thus cannot be oxidized
Metabolic Pathway B: Yes. Sulfate conjugation is a Phase II metabolic transformation.
Sulfate conjugation can occur with aromatic amines. The structure of venetoclax contains
two aromatic amines.
Metabolic Pathway C: Yes. Oxidative N-dealkylation is a Phase I metabolic transforma-
tion. As discussed in Question 1, venetoclax has six possible oxidative N-dealkylation
sites. The metabolite shown below results from oxidation at the least sterically hindered
(or most accessible) site.
450 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
Metabolic Pathway D: Yes. Glucuronic conjugation is a Phase II metabolic transformation.
Glucuronide conjugation can occur with the sulfonamide (shown), the tertiary amine, and
the two aromatic amines. It should be noted that due to steric hindrance and the electron
withdrawing properties of the nitro group, glucuronide conjugation of venetoclax is a minor
metabolic pathway.
Metabolic Pathway E: Yes. Hydrolysis is a Phase I metabolic transformation. The bond
between the benzyl carbonyl and the sulfonamide can be hydrolyzed.
Metabolic Pathway F: No. Alkene oxidation is a Phase I metabolic transformation that can
occur with nonaromatic carbon-carbon double bonds. Although the structure of venetoclax contains a double bond in the cyclohexene ring, neither carbon atom involved in this
double bond bears a hydrogen atom. Thus, this metabolism cannot occur.
3. All three of these phenyl rings are either electronically deactivated and/or sterically hindered, thus minimizing the probability that they would undergo aromatic oxidation. The
para-chloro phenyl ring is very accessible to metabolism; however, the electron withdrawing chloro group deactivates the ring. The aromatic ring in the middle of the molecule is
attached to both electron withdrawing groups (the carbonyl) and electron donating groups
(the ether oxygen and the aromatic amine); however, due to its position in the molecule
and the size of the rings and chains to which it is attached, it is not very accessible to
metabolizing enzymes. It is thus highly unlikely that aromatic oxidation would occur here
at this aromatic ring. Similarly, the aromatic ring with the nitro group is highly sterically
hindered and not very accessible. Additionally, the nitro group is a strong electron withdrawing group and electronically deactivates the ring from aromatic oxidation.
4. There are two sites of metabolic transformation: the nitro group and the tetrahydropyran
ring (i.e., the oxygen containing alicylic ring). The nitro group is first reduced to a primary
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 451
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aromatic amine. This is followed by acetylation. The tetrahydropyran ring first undergoes
oxidative O-dealkylation to give a primary hydroxyl group and an aldehyde. The aldehyde
is further oxidized by ALDH enzymes to a carboxylic acid. The carboxylic acid then undergoes amino acid conjugation to yield the final metabolic product.
Checkpoint Drug 2: Elamipretide
1. The cLog P for elamipretide is 0.3677, which indicates significant water solubility (the
amount of hydrophilic character of guanidine, primary amines, phenol, and multiple
amides is greater than the hydrophobic character of phenol, aromatic hydrocarbon).
The ability of the guanidine and two primary amines to be predominantly ionized in most
physiologic environments contributes to the overall water solubility of elamipretide.
Because renal elimination requires a drug to be highly water soluble, it is likely that elamipretide can be eliminated without the need for Phase I or Phase II metabolic transformation.
No, a Phase I transformation does not need to occur prior to a Phase II transformation.
2.
The two primary amines can directly undergo a Phase II acetylation transformation as well
as a Phase II N-methylation. The phenol can directly undergo a phase II POMT catalyzed
O-methylation as well as Phase II sulfation and glucuronidation transformations.
3. Primary amine (amino terminus): oxidative deamination; N-oxidation
Primary amine (lysine): oxidative deamination; N-oxidation
Phenol: benzylic oxidation of CH
hydroxylation (ortho, para)
Aromatic hydrocarbon: benzylic oxidation of CH2 (prochiral carbon); aromatic hydroxyla-
tion (ortho, para)
4. This prodrug must undergo the following metabolic transformations to become the active
drug:
Primary amine (amino terminus): amide hydrolysis
Phenol: oxidative-O-dealkylation
; benzylic oxidation of CH2 (prochiral carbon); aromatic
3
Review Questions
1. Part A: para and ortho aromatic hydroxylation; oxidative O-dealkylation; oxidative
N-dealkylation; N-oxidation; amide hydrolysis; alcohol oxidation
Part B: Metabolic products are shown below.
Part C: Phase II metabolic transformations can occur on the primary alcohol. If this func-
tional group were replaced by an SH group, then potential H-bonding interactions could
still occur, but Phase II metabolic transformations could not occur.
452 BASIC CONCEPTS IN MEDICINAL CHEMISTRY
2. Part A: The ether that can participate in oxidative O-dealkylation has been boxed.
Part B: The crossed-out ether cannot undergo oxidative O-dealkylation because the carbon
atoms attached to the ether oxygen atom do not bear any hydrogen atoms and therefore
cannot undergo oxidation.
Part C: The boxed halogenated aromatic hydrocarbon cannot undergo para aromatic
hydroxylation because there is a fluoro substituent in the para position. As a result, the
carbon atom at the para position does not bear a hydrogen atom and is not eligible for
oxidation.
Part D: The functional groups that can undergo hydrolysis are circled below.
3. All possible Phase I metabolic transformations are provided below.
APPENDIX - ANSWERS TO CHAPTER QUESTIONS 453
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Names of Phase I transformations possible:
Aromatic hydroxylation (ortho)
Oxidative deamination
Amide hydrolysis
S-dealkylation
Epoxidation/peroxidation
Allylic oxidation
4. Part A: Yes, treprostinil can undergo benzylic oxidation.
Part B: No, Atecegatran cannot undergo benzylic oxidation. There is one benzylic carbon
(circled atom) present in the molecule, however it is attached to a nitrogen heteroatom. As
a result, benzylic oxidation does not occur.
5. Potential Phase I and Phase II metabolic transformations are provided below.
Dobutamine Hydroxyzine Fludrocortisone Tolvaptan
para/ortho Aromatic
hydroxylation
Oxidative N-dealkylation Oxidative N-dealkylation Alcohol oxidation Omega-1 oxidation
Oxidative deamination N-oxidation Reduction para/ortho Aromatic
Benzylic oxidation Oxidative O-dealkylation Benzylic oxidation
Phase II: Sulfation Alcohol oxidation N-oxidation
Phase II: Glucuronidation Phase II: Glucuronidation Phase II: Glucuronidation Phase II: None directly
Phase II: Methylation Phase II: Sulfation Phase II: Sulfation
para/ortho Aromatic
hydroxylation
Allylic oxidation Omega oxidation
hydroxylation
(aromatic heterocycle)
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