Nitrosoureas from chemist to physician: classification and recent approaches to drug design

Molecular design of chemotherapeutic nitrosoureas is reviewed in the light of a chemical classification of N-(2-chloroethyl)-N-nitrosoureas (CNUs), particularly those recently introduced and earlier compounds tested in the clinic. Of the six categories, three are rather arbitrarily based on physicochemical properties: the original, lipid-soluble drugs, water-soluble sugar derivatives, and amides of intermediate character. Others deal with more complex drug designs incorporating antimetabolites (5-fluorouracil), steroids, redox delivery systems, or hypoxia-selective 2-nitroimidazoles. Current attempts to modify the standard 2-chloroethyl group, with implications for interstrand cross-linking of DNA, are considered. Two unfortunate factors influencing the choice of drugs for clinical trial have been prejudice from the physician and commercial interests. The latter requires no further comment, but a strong plea is made for recognition of the CNU group as one of comparatively few valuable tools for rational drug design requiring appropriate pharmacokinetic evaluation, rather than as a somewhat boring hallmark of repetitive chemists.