Rn

FIGURE 5.5 DNA cross-linking by nitrogen mustards.

2.4. Site-directed nitrogen mustards

Because of their high toxicity, considerable effort has been devoted to the development of site-directed mustards. Initial strategies were based on the incorporation of moieties that were expected to be accumulated preferentially in tumor cells. Thus, melphalan, which contains an l-phenylalanine unit, was postulated to concentrate in melanomas, since melanin is a product of phenylalanine metabolism. Although the original rationale was not correct, melphalan is used in certain types of bone marrow tumors, such as multiple myeloma, and ovarian or breast cancers. The main role of the side chain is to facilitate drug uptake by employing two amino acid transport system to enter tumor cells, that is, the sodium-independent l-amino acid system and the sodium-dependent ASC system for alanine, serine and cysteine. Other compounds designed on similar principles are uracyl mustard and estramustine, which consists of a p-estradiol unit linked to a nitrogen mustard portion via a carbamate bridge.

Melphalan (L-Phenylalanine mustard)

Melphalan (L-Phenylalanine mustard)

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