Fundamentals of Medicinal Chemistry

of folic acid to DHF and DFH to THF (see Figures 7.9 and 7.12). Trimethoprim

binds to bacterial DHFR but not human DHFR because of differences in the

structures of these enzymes due to difference in species (Appendix 12). These

observations led to the development of co-trimoxazole, a mixture of one part

trimethoprim and five parts sulphamethoxazole, to treat bacterial infections

Sulphamethoxazole Trimethoprim

Blocks this

step

Blocks this

step

PABA Folic acid DHF THF

Blocks this

step

CH 2

NH 2

N

N

H 2 N

OCH 3

OCH 3

OCH 3

SO 2 NH CH 3

NO

H 2 N

Figure 7.12 Sequential blocking using sulphamethoxazole and trimethoprim

7.5.3 Intercalation agents

Intercalating agents are compounds that insert themselves between the bases of

the DNA helix (Figure 7.13(a) ). The insertion causes the DNA helix to partially

unwind at the site of the intercalated molecule. This inhibits transcription, which

blocks the replication process of the cell. Although the mechanism of this

inhibition is not known, inhibition of cell replication can lead to cell death

and an improvement in the health of the patient.

The DNA begins

to unwind

Intercalating

agent

Normal DNA

(a)

Cl N

NHCHCH 2 CH 2 CH 2 N

CH 3

CH 2 CH 3

CH 2 CH 3

Chloroquine (antimalarial)

O

O

OH

OH

NH(CH 2 ) 2 NH(CH 2 ) 2 OH

NH(CH 2 ) 2 NH(CH 2 ) 2 OH

Mitoxantrone, Novanatrone*

(anticancer)

H 2 N N NH 2

Proflavine (3,6-diaminoacridine)

(antibiotic)

CH=CH 2

CH 3 O

HO N

N

H

H

Quinine (antimalarial)

(b)

Figure 7.13 (a) A schematic representation of the action of intercalation agents. The horizontal

dotted lines represent the complementary base pairs. The rings of these bases and the intercalating

agent are on edge to the reader. (b) Examples of intercalating agents.*Trade name

DRUGS THAT TARGET NUCLEIC ACIDS 151