Fundamentals of Medicinal Chemistry

O

N

O N

H F

Deoxribose-5'-Phosphate

O

N

O N

H

DNA

Deoxyribose-5'-Phosphate

O

N

Deoxribose-5'-Phosphate

(dUMP) (dTMP)

ON

Various steps H CH 3 Various steps

N^5 ,N^10 −Methylenetetrahydrofolic acid (MeTHF)

Fluorocil is metabolized by
the same route to 5-fluoro-
2-deoxyuridylic acid (FUdRP)

FUdRP inhibits the

enzyme that catalyses the

transfer of the methyl group.

The fluorine group blocks the

transfer to the 5 position on

the purine nucleus.

(DHF)

Figure 7.10 The intervention of fluorouracil in pyrimidine biosynthesis

7.5.2 Enzyme inhibitors

Enzyme inhibitors may inhibit the enzymes directly responsible for the forma-

tion of nucleic acids. For example, the topoisomerases, a group of enzymes

that are responsible for the supercoiling, cleavage and rejoining of DNA, are

inhibited by a number of compounds (Figure 7.11). This inhibition is believed to

prevent DNA transcription, which ultimately leads to cell death, which explains

the use of these drugs to treat cancer.

Amsacrine Camptothecin

SO 2 CH 3

CH 3 O

HN

H 3 C

HO O

O

N

O

N

N

H CH 3

CH 3

N

Ellipticine

Figure 7.11 Examples of topoisomerase inhibitors. Ellipticene acts by both intercalation

and inhibition of topoisomerase II enzymes. It is active against nasopharyngeal carcinomas.

Amsacrine is used to treat ovarian carcinomas, lymphomas and myelogenous leukaemias.

Camptothecin is an antitumour agent

A wide range of compounds also inhibit a number of the enzyme systems that

are involved in the biosynthesis of purines and pyrimidines in bacteria. For

example, sulphonamide bacteriostatics inhibit dihydropteroate synthetase,

which prevents the formation of folic acid in both humans and bacteria. How-

ever, although both mammals and bacteria synthesize their folic acid from

PABA (Figure 7.12), mammals can also obtain it from their diet. In contrast,

trimethoprim specifically inhibits bacterial DHF, which prevents the conversion

150 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS