Nucleic Acids in Chemistry and Biology

The following section will focus on antimetabolites while parts of Chapters 8 and 9 will deal with other
chemotherapeutic agents. The limited selectivities shown for cancer cells in the examples that follow are
sometimes based on slightly different transport properties between cell types, or perhaps on a salvage path-
way that is working at a higher level or the change in pH or oxygen tension due to the rapid metabolism of
a tumour cell.

3.7.1.1 Antimetabolites.120,122,123 Antimetabolites are structural analogues of naturally occurring com-

pounds that interfere with the production of nucleic acids. They work through a variety of mechanisms includ-
ing competition for binding sites on enzymes and incorporation into nucleic acids. Antimetabolites inhibit
the growth of the most rapidly proliferating cells in the body (e.g.bone marrow, G.I. tract, etc.). There are
three categories of antimetabolites: purine analogues, pyrimidine antimetabolites and antifolates.

3.7.1.1.1 Thiopurines. The purine analogues 6-mercaptopurineand 6-thioguanine(Figure 3.84)

are used in cancer chemotherapy, particularly against childhood acute lymphoblastic leukaemia. These
drugs are analogues of hypoxanthine and guanine, respectively. These antipurines can inhibit nucleotide
and nucleic acid synthesis, can be incorporated into nucleic acid and can sometimes do both. Most studies
indicate that the thiopurines work at multiple sites and that their mechanism of action is a result of combined
effects at these different sites. Their biological activity relies on their conversion into the corresponding
nucleoside 5-triphosphates by the salvage enzyme HGPRT. This causes feedback inhibition of amidophos-
phoribosyl transferase in the synthesis of 5-phosphoribosylamine from PRPP (Figure 3.71) and also prevents
IMP being converted into XMP and adenylosuccinate (Figure 3.73). The mononucleotide derivatives are
ultimately converted into triphosphates, which can be incorporated into RNA and DNA.

3.7.1.1.2 Deoxyadenosine Analogues. Cladribineand the more soluble fludarabine(Figure 3.85)

are used in the treatment of hairy-cell leukaemias (HCL) and chronic lymphocytic leukaemia (CLL),
respectively. Both compounds are typically given intravenously, which in the case of the former compound
leads to rapid dephosphorylation by serum phosphatases. Following cellular uptake by the target cells, the
free nucleosides are phosphorylated by deoxycytidine kinase and further phosphorylated by cellular
kinases to the triphosphates, which are then incorporated in DNA. Once incorporated into DNA, both
compounds lead to chain termination of DNA replication and ultimately to cell death. Furthermore, the
triphosphates are known to inhibit ribonucleotide reductase, thereby reducing the available pool of natural

126 Chapter 3

N

HN N

N

H

S

N H 2 N

HN N

N

H

S

6-mercaptopurine 6-thioguanine

Figure 3.84 Anti-cancer drugs 6-mercaptopurine and 6-thioguanine

O

HO

HO

N

N

N

N

NH 2

Cl

O

HO

HO

N

N

N NH

OH

OH

P

O

O

O

O

O

HO

N

N

N

N

NH 2

F

Fludarabine Cladribine Pentostatin

Figure 3.85 Anti-cancer drugs based on adenosine

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