Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
Answers to end-of-chapter questions
1) The ability of a molecule to cross the fatty cell membrane has little to do with its
size, but more with its hydrophobic character.
Oestrone is more hydrophobic than adrenaline since it has a larger carbon skeleton
and only two polar functional groups. Thus, the molecule is hydrophobic in character
and can dissolve through the fatty cell membrane.
Adrenaline has four polar functional groups and a much smaller carbon skeleton.
Thus, the polar functional groups dominate in determining the character of the
molecule making it very polar and unlikely to pass through the cell membrane.
Ketone
Phenol
HO
Phenol
HO
Adrenaline
CH3 O
Alcohol
OH
NHMe
Amine
Phenol
HO
Oestrone (or estrone)
There is another factor which makes it difficult for adrenaline to cross the cell
membrane. In aqueous solution, the four polar groups will be highly solvated with
water molecules. In order to cross the cell membrane, these water molecules have to
be 'stripped away' and this involves an energy penalty. The energy of desolvation for
oestrone would be less since it has only two polar functional groups solvated.
2) Valinomycin has a macrocylic structure where carbonyl oxygens are pointed
towards the centre, making this area polar and capable of accommodating a polar ion.
The outside of the ring is dominated by alkyl side chains which are hydrophobic in
nature. As a result, the molecule can dissolve easily in fatty cell membranes and
encapsulate polar ions, allowing these ions to be transported across cell membranes.
Further details are provided in section 10.6.2.
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Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
L-Valine
Me
H
NH
L-Lactate
Me
H
O
Me
O
L-Valine
H Me
O
O
O
O
O
Me
acid
Me
O
H
D-Hyi =
D-Hydroxyisovaleric
NH
HN
L-Valine
H
O
O
Me
D-Hyi
Me
Polar
centre
O
O
Hydrophobic
side chains
O
O
H
H
Me
H
O
Me
NH
O
O
HN
Me
D-Valine
Me
O
Me
D-Valine
Me
H
Me
D-Hyi
Me
L-Lactate
Me
NH
H
H
Me
Me
H
L-Lactate
Me
Me D-Valine
D-Hyi
Valinomycin
3) The alkyl chains are linked to the glycerol skelton by ether linkages rather than by
ester linkages. Ethers are chemically more stable than esters to extreme conditions.
ether link
Branching
Branching
Branching
O
Branching
O
O
H
P
OCH2CH2NH3
O
O
glycerol
skeleton
ether link
The long alkyl chains are also branched, unlike those in eukaryotic cell membranes.
Branching makes the chains more resistant to oxidation.
4) The alkyl group is hydrophobic and is embedded into the cell membrane. As a
result, the drug is anchored to the cell membrane and is located on its outer surface
such that it is ideally located to interfere with cell wall synthesis. Further details can
be found in section 19.5.5.2.
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Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
HO
Alkyl anchor
CH2OH
O
HO
O
N
H
OH
HO
O
O
NHAc
C
HO
D
O
O
O
Cl
O
E
OH
Cl
O
H
N
H
N
H H
N
O
N
H
O
CO2
H
O
H
NH3
O
H
N
N
H
H
H
B
HO
OH
HO
A
O
HO
O
OH
O
OH
HO
OH
Teicoplanin
Alkyl chain anchor
Cell membrane
5) A hydrophobic chain could be attached to the Ras protein which would serve to
anchor it to the inner surface of the cell membrane, in the same way in which
teicoplanin is anchored to the outer surface of cell membranes (compare answer 4
above). The actual process by which a hydrophobic chain is attached to the Ras
protein is shown below where the chain is attached to a cysteine residue. More details
can be found in section 21.6.1.
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Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
Val
Met
O
Ras
H
N
O
H
N
N
H
Cys
HS
S
O
OH
N
H
O
Ras
O
H
N
O
H
N
N
H
S
O
S
O
FTase
PPO
farnesyl diphosphate
Further processing
O
Ras
H
N
OMe
Methyl ester
S
6) Cholesterol has one polar group - the alcohol group. This can form a H-bond to the
polar head group of phospholipids. The rest of the molecule is hydrophobic and will
sink into the cell membrane to form hydrophobic interactions with the alkyl side
chains of the phospholipids.
Polar
Head
Group
OH
CH3
Hydrophobic Tails
CH3
H
OH
N
H
CH3
H
H3C
CH3
7) cis-Double bonds introduce a kink into the chain which will hinder the regular
packing of the hydrophobic chains. This increases the fluidity of the cell membrane.
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Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
NMe3
NMe3
(CH2)2
(CH2)2
O
O
O
O
P O
P
O
O
O
CH2
O
CH
CH2
O
O
CH2
O
O
cis
CH
CH2
O
O
O
trans
8) The relative order of H-bonding strength is shown below
O
O
C
O
R
RHN
C
O
R
R
C
O
R
RO
C
R
Increasing strength of carbonyl oxygen as a hydrogen bond acceptor
This reflects the fact that the greater the electron density on the carbonyl oxygen, the
stronger it will act as a hydrogen bond acceptor.
The carboxylate group is the strongest hydrogen bond acceptor since a full negative
charge is shared between both oxygens.
The carbonyl oxygen of the amide will also act as a good hydrogen bond acceptor
since the lone pair of electrons on nitrogen can interact with the carbonyl group to
increase electron density on the carbonyl oxygen as shown below.
O
R
N
H
C
O
R
R
N
H
C
R
Amide - N acts as poor HBA
O acts as a good HBA
No such interaction occurs for the ketone or ester carbonyl groups, but the carbonyl
groups are still polarised resulting in the oxygen having a slightly negative charge.
Consequently the carbonyl oxygen in these functional groups can still act as a
hydrogen bond acceptor, but less strongly.
9) The diagram below shows the possible intermolecular bonding interactions for the
various functional groups present in each molecule (HBA = hydrogen bond acceptor;
HBD = hydrogen bond donor; vdw = van der Waals interactions)
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Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
HBA
HBD O
H
HBD
H HBA
O
vdw
H
HBD O
HBA
Adrenaline
H3C H
HBA
CH3 O
dipole-dipole
HBD
H
N HBA
Me
CH3
CH3
H
CH3
HBD
H
vdw
O
HBA
HBD
H
vdw
O
HBA
Oestrone
Cholesterol
Notes
* It cannot be assumed that all the interactions shown actually occur.
* Adrenaline can also exist in the ionised form below, resulting in the potential
interactions shown
HBD
H HBA HBD
O
H
HBA
H HBD
HBD O
N
H
Me
ionic
vdw
H
HBD O
HBA
Adrenaline
* The remainder of the carbon skeleton in each molecule has the potential to interact
with other hydrophobic molecules through van der Waals interactions. This is
particularly the case for the steroid structures.
10) Trade names are in brackets
Amoxicillin (Amoxil)
H2N
H
H H
N
O
HO
Phenol
H
S
N
Me
Me
O
CO2H
Ranitidine (Zantac)
Me2N
4
5
3
CHNO2
2
O
S
N
H
NHMe
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CH3
Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 1 – Drugs and drug targets: an overview
Gefitinib (Iressa)
F
HN
Cl
O
O
N
N
N
OMe
Atracurium (Tacrium)
MeO
MeO
OMe
N
Me
O
O
OMe
OMe
H
O
N
OMe
O
MeO
OMe
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