Pharmacological Importance of Chiral Separations - Chiral Separations by Capillary Electrophoresis - page 11

OH

N

N

*

O

O O N O

N

FIGURE 1.7 p -Hydroxylation of phenytoin. Asterisks indicates chiral center.

O

HO

*

N

N

O

O

NH 2 NH 2

(a) (b)

FIGURE 1.8 Structure of (a) oxcarbazepine and (b) licarbazepine. Asterisks indicate the
chiral center.

An example of product stereoselectivity is the aromatic p -hydroxylation of one of
the phenyl rings of phenytoin, creating a chiral center at C-5 of the hydantoin ring
(Figure 1.7) [31,34]. A second example is the antiepileptic drug oxcarbazepine. In
humans, this achiral prodrug is rapidly reduced in the liver to the pharmacologically
active and chiral metabolite 10-hydroxycarbazepine or licarbazepine (Figure 1.8).
This metabolic reduction is stereoselective, resulting in a 4:1 ratio between the active
S -enantiomer and R -licarbazepine [39,47].

1.4.3.3 Substrate-Product Stereoselectivity
Substrate-product stereoselectivity means the stereoselective metabolization of
one of the enantiomers whereby another chiral center is introduced and diastere-
oisomers are thereby formed. Warfarin is metabolized via two principal routes:
aromatic hydroxylation of the coumarin ring (see substrate stereoselectivity) and
ketone reduction in the side chain that produces a new chiral center (Figure 1.9).
The latter pathway shows marked substrate stereoselectivity for the R -enantiomer,
as well as product stereoselectivity, namely, the formation of alcohols of the
S -coni guration [23,33,48].

CH 3 CH 3

O * OH

OH OH

* *

O O O O

FIGURE 1.9 Structure of warfarin and warfarin alcohol. Asterisks indicate the chiral center.