Figure 1 Chemical structures of sulfur mustard (1) and mechlorethamine (2).

systematic toxicity of 1 was unacceptable, even upon direct injection into the tumor tissue.2 Therefore, a less toxic mustard was sought, and eventually yielded the isoelectronic mustard mechlorethamine (Mustargen, 2). The antitumor properties of 2 had been determined as early as 1942; however, the information was not published until 1946.3 In that seminal paper, 2 was disclosed as being most effective against Hodgkin's disease. This disclosure has been widely recognized as the advent of modern cancer chemotherapy.

During the past 60 years, the focus of the medicinal chemist has been not only to understand better the mechanism of cytotoxicity of 1 and 2, but also the discovery of safer, more selective chemotherapeutics. As a result, a variety of structurally distinct chemotypes have emerged that possess the desired cytotoxic properties, yet in some cases have dramatically reduced toxicity. The structural classes that will be the focus of this discussion are: (1) nitrogen mustards, (2) oxazaphosphorine mustards, (3) triazenes, (4) nitrosoureas, (5) mitomycins, and (6) platinum complexes. A key feature of these classes of compounds is their ability to alkylate key endogenous nucleophiles, principally DNA.

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