Answers Ch02

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 sp 3 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
OH
O
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
MethylDglucose
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 H i g h e r E d u c a t i o n
Oxford University Press, 2006. All rights reserved.

Ketone
CH O
Alcohol
OH
Phenol
HO
NHMe
Amine
Phenol
HO
Phenol
HO
Adrenaline
Oestrone(orestrone)
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.
LValine
DHyi
Me
Me
DValine
Me
LLactate
Me
NH
O
O
Me
Me
LLactate
Me
Me
NH
Me
O
O
LValine
Me
LValine
O
O
O
Me
DHyi
NH
NH
H
H
Me
H Me
Me
O
Hydrophobic
sidechains
HN
Me
Me
Polar
centre
H
Me
H
O
HN
DValine
Me
Me
DHyi=
DHydroxyisovalericacid
LLactate
Me
Me DValine
DHyi
Valinomycin

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.
etherlink
Branching
Branching
Branching
Branching
O
O
OCH2CH2NH3
O
glycerol
skeleton
etherlink
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
Alkylanchor
CH2OH
O
HO
N
H
OH
HO
HO
O
O
O
NHAc
C
O
O
Cl
O
D
OH
Cl
O
H
N
H
N
H H
N
B
A
HO
O
HO
O
N
H
CO2
O
O
H
NH3
H
H
OH
HO
O
OH
O
OH
HO
OH

Teicoplanin
Alkylchainanchor
Cellmembrane
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
S
N
H
OH
Ras
H
N
O
N
H
H
N
O
S
N
H
FTase
PPO
farnesyldiphosphate
Ras
H
N
Furtherprocessing
O
OMe
Methylester
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.
OH
O

Polar
Head
Group
OH
CH3
HydrophobicTails
CH3
CH3
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
P O
O
CH2
O
CH
O
CH2
CH2
O
cis
CH
CH2
O
O
trans
9) The relative order of H-bonding strength is shown below

O
O
O
R
RHN
O
R
O
R
RO
Increasingstrengthofcarbonyloxygenasahydrogenbondacceptor

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
O
R
N
H
AmideNactsaspoorHBA
OactsasagoodHBA
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
dipoledipole
HBD
H
N HBA
Me
CH3
CH3
H
CH3
HBD
H
vdw
O
Oestrone
HBD
H
O
HBA
vdw
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
CH3

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.

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Patrick: An Introduction to Medicinal Chemistry 3/e

Chapter 2: The why and the wherefore drug targets

Patrick: An Introduction to Medicinal Chemistry 3/e

Patrick: An Introduction to Medicinal Chemistry 3/e

Patrick: An Introduction to Medicinal Chemistry 3/e

Patrick: An Introduction to Medicinal Chemistry 3/e

9) The relative order of H-bonding strength is shown below

Patrick: An Introduction to Medicinal Chemistry 3/e

Patrick: An Introduction to Medicinal Chemistry 3/e

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