Drug Metabolism in Drug Design and Development Basic Concepts and Practice

8. Glutathione

conjugation(Dagnino-Subiabreet al., 2000)

HO HO

NH

2

NH

2

NH

2

HO HO

S

O

HN

HO

O

NH

O

OH

O

The C-5 aromatic proton

was missing and thecoupling pattern of theremaining two aromaticprotons changed to a1.8 Hz doublet

The position of the GSH attachment

could be confirmed by an NOEexperiment. NOE may beobserved between the

b

-methylene

of the cysteine and the aromaticC4 proton. The

H

1 

C

13

HMBC

experiment may also help. Thisexperiment requires require

>

100 ug

of the metabolite

The

b-methylene of the

cysteine shifted from2.87 to 3.10 ppm

9. Methylation

(Basker et al.,1990)

HO HO

O

NH

N

S

HN HN

COOH

SN

S N

O

OH O

N

O N

O

HO O

ONH

N

S

HN HN

COOH

S

SNN

O

OH O

N

O N

O

Analo

g of Catecholic Cephalosporin

A new sharp methoxyl

signal at

d3.86

(s, 3H) ppm wasobserved

The structure was confirmed by

HMBC and NOE experiments

10. Sulfation

(Daykin et al.,2005)

OH

OH

HO

OSO

H 3 OH

HO

Py

ro

gallol

dih

ydrox

yp

hen

yl-2-O-sulfate

All three aromatic protons

shifted slightly downfield.H4 and H6 protonsshifted by 0.10 ppm andthe H5 shifted by 0.21 ppm

No further experiments can be

performed due to lack of NMRactive nuclei in the –SO

H group. 3

The aromatic protons

of the metabolite showedtwo groups of signals asdid the parent compound,which is consistent withthe symmetrical metabolite formed by sulfationat the C2 hydroxyl

(continued

)

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