A nitrogen mustard prodrug, cyclophosphamide (7.65), was synthesized in the hope
of exploiting the high level of phosphoramidase enzymes in certain tumor cells.
Cyclophosphamide is relatively nontoxic but is metabolized in the liver, not the tumor,
to form the active drug, the phosphoramide mustard (7.66). Whilst not without side
effects, cyclophosphamide is a relatively successful drug in a number of carcinomas
and lymphomas. Ifosfamide (7.67) is an analog of cyclophosphamide; it is structurally
related to the nitrogen mustards except that the two chloroethyl arms are not attached
to the same nitrogen.
The mode of action of these compounds is nonspecific, because the active species,
the resonance-stabilized carbonium ion, reacts with any nucleophilic centre, including
water. Consequently, there is a tremendous waste of drug on the way to the site of
action, through hydrolysis alone; this waste is slowed with the aromatic compounds like
melphalan. The principal target of the nitrogen mustards seems to be the 7-nitrogen of
guanine in DNA, which crosslinks the two strands. This action prevents unwinding,
causes deguanylation and base-mispairing, and compromises the template function of
DNA. Linking within the same strand and binding to nucleoprotein or the phosphate
anion are also possible effects and can lead to functional damage in rapidly proliferat-
ing cells, like miscoding and point mutations. The chemistry of the alkylating process
is shown in figure 7.6.
Nitrosoureas. The nitrosoureas, represented by carmustine (7.68, BCNU), lomustine
(7.69, CCNU), and semustine (7.70, methyl-CCNU), are more recent discoveries.
These compounds are relatively easily prepared; for example, carmustine is synthesized
by treating 1,3-bis(2-chloroethyl)urea with sodium nitrite and formic acid. These drugs
combine the N-NO group with a monofunctional mustard. They function by crosslink-
ing through alkylation of DNA. The compounds are effective against some brain tumors
and certain lung carcinomas, both of which tend to respond poorly to chemotherapy. It
is their relatively unique lipid-soluble properties that enable these compounds (unlike
many chemotherapeutics) to cross the blood–brain barrier. Streptozotocin (7.71) is a
naturally occurring glucosamine nitrosourea derivative that shows antileukemic activity
as well as antibiotic effects. The nitrosoureas can carbamoylate proteins (e.g., on lysine)
by forming isocyanates, whereas the chloroethyl carbonium ion formed could potentially
crosslink the strands of DNA.
Alkylsulphonate Esters.Methanesulfonate esters such as busulfan (7.72) produce
clinical remission in chronic myelogenous leukaemia. Busulfan acts through an SN 2
nucleophilic displacement and presumably crosslinks DNA, since the methanesulfonate
448 MEDICINAL CHEMISTRY