Fundamentals of Medicinal Chemistry

the biosynthesis of purines and pyrimidines (Figure 7.9). In addition, DHFR

also catalyses the conversion of folic acid to DHF.

COOH

CONHCHCH 2 CH 2 CO OH

n

Dihydrofolate

reductase

(DHFR)

Dihydrofolate

reductase

(DHFR)

O

N NH 2

H

N

N

N

R

HH

H

H

NCH 2

O

N NH 2

H

N

N

N

R

NH

HH

H

H

H

THF

O

N NH 2

H

N

N

N

R

NH

HH

H

DHF

dUMP dTMP

O

N NH 2

H

N

N

N

R

NH

HH

H

H

H

Folic acid

N^5 ,N10-methylene-THF

Serine

hydroxymethyl

transferase

Thymidylate

synthase

O

O N

N

HO

O

H

H

O

HO

HO

P

CH 3

O

O N

N

HO

O

H

H

O

HO

HO

P

CH 2 COOH

NH 2

Glycine

Serine

HOCH 2 CHCOOH

NH 2

Key:R =

In Mammals

Figure 7.9 An outline of the synthesis of deoxythymidylate monophosphate (dTMP) from

2-deoxyuridylate monophosphate (dUMP). N^5 ,N^10 -methylene-THF is the source of the methyl

group in the conversion. Antifolates such as methotrexate inhibit DHFR

Purine antimetabolites are exogenous compounds, such as 6-mercaptopurine

and 6-thioguanine, with structures based on the purine nucleus. They inhibit the

synthesis of DNA and in some cases RNA by a number of different mechanisms.

Pyrimidine antimetabolites have structures that closely resemble those of the

endogenous pyrimidine bases. They usually act by inhibiting one or more of the

enzymes that are required for DNA synthesis. For example, fluorouracil is me-

tabolized by the same metabolic pathway as uracil to 5-fluoro-2’-deoxyuridyline

monophosphate (FdUMP). FdUMP inhibits the enzyme thymidylate synthetase,

which is responsible for the transfer of a methyl group from N

5

,N

10

-methylene-

THF to the C5 atom of deoxyuridylate (dUMP) (Figure 7.9). The FdUMP binds

to the enzyme but the presence of the unreactive C5-F bond in FdUMP blocks

methylation of the FdUMP and as a result the formation of deoxythymidylate

monophosphate (dTMP) and its subsequent incorporation into DNA (Figure

7.10). Fluorine was chosen to replace hydrogen at the C5 position because it is

of a similar size to hydrogen (atomic radii: F, 0.13 nm, H, 0.12 nm). It was thought

that this similarity in size would give a drug that would cause little steric disturb-

ance to the biosynthetic pathway. In other words, the FdUMP would be the

correct size and shape bind to the same active site of the enzyme as dUMP.

Analogues containing larger halogen atoms do not have any appreciable activity

because they are too large to bind effectively to the actve site of the enzyme.

DRUGS THAT TARGET NUCLEIC ACIDS 149