ion in an excellent leaving group. Busulfan is synthesized by treating 1,4-butanediol
with methanesulfonyl chloride in the presence of pyridine.
Aziridines. This class of compounds includes agents such as thiotepa (7.73) and
triethylenemelamine (7.74). These compounds contain reactive three-membered nitrogen-
containing heterocycles that react with nucleophiles to relieve ring strain. The aziridine
group is protonated to provide a reactive aziridinium ion that is known to alkylate
DNA. Thiotepa is synthesized by treating trichlorophosphine sulphide with aziridine.
Altretamine (7.75, hexamethylmelamine) is a structural analog of triethylenemelamine
that is useful as an alkylating agent in the treatment of ovarian carcinoma.
A variety of other therapeutic compounds have mechanisms that probably involve
alkylation. Procarbazine and dacarbazine are the two most successful agents in this group.
Dacarbazine is a synthetic compound that functions as an alkylating agent, following
metabolic activation by liver microsomal enzymes, to yield diazomethane. It has been
used successfully in the treatment of sarcomas.
ENDOGENOUS CELLULAR STRUCTURES 449Figure 7.6 Alkylating agents as antineoplastic drugs: the compounds covalently link to both
strands of the DNA, literally holding them together. This prevents the DNA from uncoiling,
a crucial early step in the process of DNA replication. This stops cellular proliferation in a rapidly
growing cell.