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Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
Answers
1) -D-Glucose and -D-glucose have different optical rotations since they are
different structures, where one of the 5 asymmetric centres present. The
anomeric carbon) has a different configuration. In solution, -D-glucose ring
opens to form an open chain form where an asymmetric sp3 carbon becomes an
sp2 hybridised carbonyl carbon. Recyclisation can occur in two ways, either
restoring the original -D-glucose or generating -D-glucose. This continues until
an equilibrium is reached when the optical rotation reaches +52.5. This
corresponds to an equilibrium mixture consisting of 64% -D-glucose and 36% D-glucose.
HOCH2
H
HO
*
HO * * O
*
*
OH OH
-anomer
HOCH2
HO
*
HO * *
*
OH
O
OH
H
H
HOCH2
HO
*
HO * * O
*
-anomer
*
OH
OH
Methyl -D-glucose has a different structure from either -D-Glucose or -Dglucose and so it has a different optical rotation. The optical rotation remains
constant in solution since the methyl group prevents the mechanism by which ring
opening takes place. Therefore, an equilibrium between two different anomers is
not possible.
HOCH2
HO
*
HO * * O
*
OH
* OMe
Methyl--D-glucose
2) The ability of a molecule to cross the fatty cell membrane has little to do with its
size, but more with its hydrophobic character.
Estrone 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.
OXFORD
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Higher Education
Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
Ketone
CH O
Alcohol
OH
Phenol
HO
3
NHMe
Amine
Phenol
HO
Phenol
HO
Adrenaline
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 estrone would be less since it has only two polar functional groups
solvated.
3) Valinomycin has a macrocylic structure where carbonyl oxygens are pointed
towards the centre, making this are 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 16.6.1.
L-Valine
Me
H
NH
O
L-Lactate
H
Me
O
Me
Me
L-Valine
H
O
Me
O
L-Valine
O
O
O
O
NH
NH
H
H
Me
H Me
D-Hyi =
D-Hydroxyisovaleric acid
Me
O
O
Me
D-Hyi
O
HN
H
Hydrophobic
side chains
H
Polar
centre
O
O
Me
O
H
Me
H
O
O
HN
D-Valine
Me
Me
NH
O
O
Me
D-Valine
Me
H
Me
D-Hyi
Me
L-Lactate
Me
Me
H
L-Lactate
Me
Me D-Valine
D-Hyi
Valinomycin
OXFORD
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Higher Education
Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
4) The alkyl chains are linked to the glycerol skeleton by ether linkages rather
than by ester linkages. Ethers are chemically more stable than esters to extreme
conditions.
ether link
Branching
Branching
O
Branching
Branching
O
O
P
OCH2CH2NH3
O
H
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.
5) 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 16.5.5.2.
HO
Alkyl anchor
CH2OH
O
HO
N
H
OH
HO
HO
O
O
O
NHAc
C
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
OH
HO
A
O
HO
H
H
H
B
HO
N
O
OH
O
OH
HO
OH
OXFORD
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Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
Teicoplanin
Alkyl chain anchor
Cell membrane
6) 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
5 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 18.6.1.
Val
Ras
H
N
Cys
HS
Met
O
N
H
H
N
O
O
S
N
H
OH
Ras
O
H
N
O
N
H
S
H
N
O
O
S
N
H
FTase
PPO
farnesyl diphosphate
Ras
H
N
Further processing
O
OMe
Methyl ester
S
7) 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.
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Higher Education
OH
O
Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
Polar
Head
Group
OH
CH3
Hydrophobic Tails
CH3
CH3
H
H
H3C
CH3
8) 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.
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
9) 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
OXFORD
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Higher Education
Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
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 it can still act as a hydrogen bond acceptor, but
less strongly.
10) 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)
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
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
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CH3
Patrick: An Introduction to Medicinal Chemistry 3/e
Chapter 2: The why and the wherefore – drug targets
HBA
HBD O
H
HBD
H HBA
O
vdw
H
HBD O
HBA
Adrenaline
HBD
H
H HBD
N
Me
ionic
* The remainder of the carbon skeleton in each molecule has the potential to
interact with other hydrophobic molecules through van der Waals interactions.
OXFORD
© Oxford University Press, 2006. All rights reserved.
Higher Education