Nucleic Acids in Chemistry and Biology

antisense technologies (Section 5.7.1),^1 studying RNA and DNA structure,2,3DNA–protein interactions
(Chapter 10) and nucleic acid catalysis (Section 5.7.3). In spite of advances in stereospecific synthesis, it
remains more economical to produce the major nucleosides by degrading nucleic acids than by total
synthesis.
Modified nucleosides are widely distributed naturally. For example, all species of tRNA contain unusual
minor bases and many bacteria and fungi provide rich sources of nucleosides modified in the base, in the
sugar or in both base and sugar residues. Since some of these have been found to show a wide and useful
range of biological activity, thousands of nucleoside analogues have been synthesised in pharmaceutical
laboratories across the world. In recent times, industrial targets for this work have been anti-viral and anti-
cancer agents. For instance, the arabinose analogues of adenosine and cytidine, araA and araC, are useful
as anti-viral and anti-leukaemia drugs, while 5-iodouridine is valuable for treating Herpes simplex infec-
tions of the eye (Figure 3.1).
D-Ribose and other pentoses are relatively inexpensive starting materials, which are especially useful in
stereochemically controlled synthesis of modified sugars. Three principal strategies for the synthesis of
modified nucleosides have been developed. These are illustrated by retrosynthetic analysis (Figure 3.2). First,
disconnection A identifies formation of the glycosylic bond by joining the sugar onto a preformed base. In
practice, this uses the easy displacement of a leaving group from C-1 of an aldose derivative by a nucleo-
philic nitrogen (or carbon) atom of the heterocyclic base. Second, the double disconnection B identifies
the process of building a heterocyclic base onto a preformed nitrogen or carbon substituent at C-1 of the

78 Chapter 3

O

HO

HO

OH

N

N

NH 2

O O

HO

HO

OH N

N

N

N

NH 2

O

HO

HO

N

NH

O

O

I

OH

ara-adenosine ara-cytidine 5-iodouridine

Figure 3.1 Modified nucleosides of biological importance

N

N NH

N

H

O

O

NH 2

X

HO

HO (O)H

N

NH

N

N

O

NH 2

HO O

HO (O)H

N

NH

N

YC

O

NH 2

HO O

HO (O)H

NH 2

Z

HO O

HO (O)H

N

N

NH 2

CY

+

+

NH 2

NH 2

+ Z

A

A

B B

C

C

Figure 3.2 Disconnection analysis of nucleoside synthesis

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