Fundamentals of Medicinal Chemistry

Antisense compounds were originally short lengths of nucleic acid chains that

had base sequences that were complementary to those found in their target

RNA. These compounds were found to be unsuitable as drugs because of poor

binding to the target site and short half lives due to enzyme catalysed hydrolysis.

At present, development is still in its early stages, but the concept has aroused

considerable interest in the pharmaceutical industry. Development is currently

taking three basic routes:

1. modification of the backbone to increase stability to hydrolysis (Figure

7.14(b));

2. changing the nature of the sugar residue (Figure 7.14(c)) and

3. modifying the nature of the substituent groups of the bases (Figure 7.14(d)).

Fluorine at 2'

F

O

BASE

H

H

H

O CH 2

O

3'

5'

2'

OR

O

H

BASE

H H

O CH 2

O

2'

3'

5'

O

O

BASE

BASE

H H

H

H

O CH 2

H

O

P

H

H

O

H

−O O CH 2

O

5'

3'

Guanidine linkage

Formacetal

O

CH 2 OCH 2

3'

5'

Peptide nucleic acid

(PNA)

CH 2

C

O

NH CH 2

5'

3'

C

H 2 N

NH CH 2

CHNH 2

5'

3'

(a) (b) (c) (d)

1 N O

NH

CH 3 O

5

Various 2'-hydroxyalkyl

ethers

5-Methylcytosine

5-(1-Propnyl)uracil

5

O

NH 2

N 1

CH 3

N

Figure 7.14 Development routes for antisense drugs. Examples of (a) a section of the backbone

of a deoxyribonucleic chain, (b) backbone modifications, (c) sugar residue modifications and (d)

base modifications

7.5.6 Chain cleaving agents

The interaction of chain cleaving agents with DNA results in the breaking of

the nucleic acid into fragments. Currently, the main cleaving agents are the

bleomycins and their analogues (Figure 7.15). These are a group of naturally

154 SELECTED EXAMPLES OF DRUG ACTION AT SOME COMMON TARGET AREAS