carcinogenic (cancer-causing) substances through precisely the same mechanism. There
is a fine line between anticancer compounds and cancer-causing compounds. Indeed,
one of the potential long-term side effects of anticancer agents is their ability to induce
cancer in a different organ system years after the original cancer has been treated.
7.8.1.2 Alkylating Agents
These antitumor agents are compounds that form carbonium ions or other reactive
electrophilic groups. Such compounds bind covalently to DNA, and either crosslink the
two strands of the helix or otherwise interfere with replication or transcription. Since
these processes are more prevalent in rapidly dividing malignant cells than in normal tis-
sues, alkylating agents can control and in some cases even eliminate tumors. However,
their selectivity is limited and they have many and serious side effects.
Bis(chloroethyl)amines (the “Nitrogen Mustards”). Alkylating agents were ini-
tially developed from “sulphur mustard,” the horrific and infamous “mustard gas” of
World War I—a lethal vesicant and cell poison. Its nitrogen analog, the nitrogen mus-
tard mechlorethamine (7.62), was first used as an antitumor agent in 1942, with some
success; numerous derivatives were subsequently developed. The rationale for this, if
any, was to use carrier molecules that are natural products, in the hope that they could
direct the active, nitrogen-mustard component of the compound to a selective metabolic
site in a tumor. Melphalan (phenylalanine mustard or 7.63) and chlorambucil (7.64)
are just two examples of many such compounds. Melphalan is synthesized by treat-
ing L-N-phthalimido-p-aminophenylalanine ethyl ester with ethylene oxide, followed
by phosphorus oxychloride, followed by acid-catalyzed hydrolysis; chlorambucil is
446 MEDICINAL CHEMISTRY