Fundamentals of Medicinal Chemistry

an enzyme in the metabolic pathway in the cell. Both these types of intervention

inhibit the targeted metabolic pathway to a level that hopefully has a significant

effect on the health of the patient.

The nature of the action of antimetabolites means that a rational starting

point for the design of new drugs is the structure of the normal metabolites used

by the cell (Table 7.5). Consequently, SAR studies based on the endogenous

metabolite supported by combinatorial synthesis and molecular modelling offer

logical routes to new lead compounds and ultimately new drugs.

Antimetabolites that are used to prevent the formation of DNA may be

classified asantifolates, purine antimetabolitesandpyrimidine antimetabolites

(Table 7.5). Antifolates are believed to inhibit dihydrofolate reductase

(DHFR). This enzyme is responsible for catalysing the conversion of dihydro-

folic acid (DHF or FH 2 ) to tetrahydrofolic acid (THF or FH 4 ), which occurs in

Table 7.5 Examples of antimetabolites

Classification and

endogenous metabolite Examples of antimetabolite Notes

Antifolates

NH

N

H

H 2 N

O

N

N

N

COGln(COOH)

COGln(COOH)

NH 2

N

N

H 2 N CH

3

N

N

N

Methotrexate

Aminopeterin

CO Gln(COOH)

NH 2

H 2 N N

N

N

N NH

Methotrexate and aminopterin

are believed to inhibit

dihydrofolate reductase by

blocking the reduction of

dihydrofolate to

tetrahydrofolate, which is the

cofactor in the synthesis of

thymine and purines used in

DNA synthesis.

Purine antimotabolites

N N

N

H

N

SH

N

N N

N

H

H 2 N

6-Mercaptopurine 6-Thioguanidine

SH

N

N N

N

H

Methyl transfer from

MeFH 4

6-Mercaptopurine acts as the

precursor of 6-thioguanosine-

5 ’-phosphate, which inhibits

several of the biochemical

pathways for the synthesis of

purine nucleotides.

6-Thioguanine is converted

into 6-thioinosine-

5 ’-phosphate, which disrupts

DNA synthesis.

Pyridine antimetabolites

O

O

HN

N

H

F

Fluorouracil

NH 2

N

O N

O

H

H

H

OH

H

HO CH 2

HO

Cytarabine

They are thought to act by

inhibiting one or more of the

enzymes required for DNA

synthesis.

148 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS