Michael E. Colvin*, Jennifer C. Sasaki and Ngoc L. Tran Pages 645 - 663 ( 19 )
The nitrogen mustard based DNA alkylating agents were the first effective anticancer agents and remain important drugs against many forms of cancer. More than fifty years of research on the nitrogen mustards has yielded a broad range of therapeutically useful compounds and a detailed knowledge of the biochemical mechanism of these drugs. Nevertheless, there is much ongoing research on the phos phosphoramidic and other nitrogen mustards to increase their potency and reduce their toxic and mutagenic side effects. To understand the existing nitrogen mustards, and to design the next generation of these drugs, more knowledge is needed about the effects of chemical modifications on their activation and selectivity. Because of the existing knowledge of these drugs, atomic-level chemical modeling can play an important role in the understanding of the phosphoramidic mustard compounds; however, it has not proved straight forward to directly relate the activity of these mustards with simple chemical properties such as bond lengths or atomic charges. Instead, quantum chemical simulations will be required to simulate the activation and alkylation reactions of these compounds, which will require the newest generation of quantum chemical and solvent modeling methods. Additionally, molecular dynamics simulations of the adducted DNA can provide data on the factors favoring crosslinking and its structural consequences. This review summarizes the extensive literature on the metabolism, activation, and action of the phosphoramidic mustards, with an emphasis on the roles that chemical modeling has and will play in the development of this important class of drugs.