Nucleic Acids in Chemistry and Biology

Other important alkylating agents used in cancer treatment include the nitrosoureas carmustine (BCNU)
and lomustine (CCNU) which alkylate the O-6 and N-1 positions of guanine bases to give N^1 ,O^6 -ethenogua-
nine (Figure 3.89),^126 which reacts to give an interstrand cross link with cytosine. Other alkylating agents
such as temozolomide (Figure 3.89) alkylate the O-6-position of guanines, which causes G→A mutations
during DNA replication. O^6 -Alkylguanine DNA alkyltransferase is a protein that can repair such DNA
damage and is expressed at elevated levels in some tumours. As a result, it is a key target for inhibition by
a number of compounds.^126 Both O^6 -benzylguanine and O^6 -(4-bromothenyl)guanine (Figure 3.89) have
been used clinically in combination with chemotherapeutic regimes that employ alkylating agents.
In all the above compounds, the therapeutic target is inhibition of DNA replication, whether by pre-
venting synthesis of precursors or by alkylating the DNA itself. As most of the effective drugs are also
toxic, patients receiving cancer chemotherapy are unusually susceptible to viral and bacterial infections.

3.7.2 Anti-Viral Chemotherapy^127

The life cycle of a virus involves a combination of its own enzymes and those of the host cell. Thus the design
of anti-viral agents can be more directly targeted than that of anti-cancer agents. Since most virus classes are
unrelated to each other and have unique replication cycles, there appears little chance for the discovery of
wide-activity anti-viral agents comparable to the broad-spectrum antibiotics, such as the
-lactams. Different
approaches have been successful for retroviruses such as HIV and DNA viruses such as HSV and hepa-
titis B virus (HBV).

3.7.2.1 Retrovirus Inhibitors. Much effort has been expended on finding a chemotherapeutic agent

to alleviate the symptoms of AIDS. The HIV is a member of the lentivirus family (a sub-class of retrovirus)
and its reverse transcriptase has been an obvious target. Virtually all the compounds currently used for the
treatment of HIV infections, or in advanced research, belong to one of four main classes:

● nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs);

● non-nucleoside reverse transcriptase inhibitors (NNRTIs);

● protease inhibitors (PIs); and

● host-cell receptor based therapeutic agents.

3.7.2.1.1 Nucleoside Reverse Transcriptase Inhibitors. There are around 40 anti-viral com-

pounds in clinical use (Table 3.2), with over half of them being used in the treatment of HIV patients. The
majority are nucleoside analogues effective against HIV or HSV infections. The key structural feature of a
nucleoside analogue as a chain terminator for RT is the absence of a 3-OH function. Thus after incorporation

Nucleosides and Nucleotides 129

N

N N

N

O

NH 2

H

N

N N

N

O

NH 2

H

N

N N

N

O

NH 2

S

Br

NN

X

O

NO H

Cl

Cl

N

N

N

N

N

O

Me

O

NH 2

N^1 ,O^6 -ethenoguanine (in DNA)

O^6 -benzylguanine O^6 -(4-bromothenyl)guanine

X = carmustine

X = lomustine

temozolomide

Figure 3.89 Structures of N^1 ,O^6 -ethenoguanine, O^6 -benzylguanine, O^6 -(4-bromothenyl)guanine and various DNA
alkylating agents