Chemistry Reference
In-Depth Information
antibiotic inactivated
by ring opening and
binding to enzyme
the common substructure
in β-lactam antibiotics
N
H
N
H
N
H
R
R
R
O
HN
O
N
O
N
O
O
O
hydrolysis
of
β
-lactam
amide bond
O
CO
2
H
CO
2
H
H
2
O
CO
2
H
H
OH
OH
Ser
Enzyme
hydrolysis of
ester function,
release from
enzyme
Ser
Enzyme
Ser
Enzyme
CO
2
H
N
H
N
H
HO
R
R
NH
2
O
HN
penicilloic acid
derivative − inactive
O
O
HO
HN
HO
2
C
Serine
CO
2
H
O
CO
2
H
H
OH
Ser
Enzyme
Ser
Enzyme
β
It is known that the nucleophilic species in a
-lactamase enzyme is the hydroxyl group of a serine residue
in the protein, and that this attacks the
-lactam carbonyl, followed by loss of the leaving group and consequent
opening of the four-membered ring. The ring-opened penicillin (or cephalosporin) becomes bound to the enzyme
through an ester linkage and is no longer active. The ester linkage is subsequently hydrolysed to release an
inactive penicilloic acid derivative and regenerate the functional
β
β
-lactamase enzyme.
-lactam ring is more susceptible to nucleophilic attack than the unstrained side-
chain amide function. However, by increasing the steric bulk of the side-chain, the approach of a
Note again that the strained
β
β
-lactamase
enzyme to the
β
-lactam ring is hindered in the semi-synthetic antibiotic, giving it more resistance to enzymic
hydrolysis.
7.11 Hydride as a nucleophile:
reduction of carboxylic acid
derivatives
the hydride itself never acts as a nucleophile because
of its small size and high charge density.
Acyl halides, anhydrides, esters
and
acids
all
react with LAH to give a
primary alcohol
. Amides
(see later) behave differently.
The initial reaction is effectively the same as
with an aldehyde or ketone, in that hydride is
transferred from the reducing agent, and that the
tetrahedral anionic intermediate then complexes with
the Lewis acid aluminium hydride. However, the
typical reactivity of the carboxylic acid derivatives
arises because of the presence of a leaving group.
We have already noted the ability of
complex
metal hydrides
like
lithium aluminium hydride
and
sodium borohydride
to reduce the carbonyl
group of aldehydes and ketones, giving alcohols (see
Section 7.5). These reagents deliver hydride in such
a manner that it appears to act as a nucleophile.
However, as we have seen, the aluminium hydride
anion is responsible for transfer of the hydride and
