Objective: Emergence of nitrogen mustards and their derivatives as DNA alkylating agent and
their expanding anti-cancer applicability did fuel up massive efforts directed towards the design of anticancer
agents in clinical practice. Considerable progress in this field has been achieved in the last few decades.
Rich panoply of literature has illustrated the rather underexploited or completely novel therapeutic
approaches based on these compounds and biological targets which are of special interest. The prime objective
of the present article is to highlight a majority of the landmark efforts been devoted into the understanding
of nitrogen mustards as DNA alkylator and focuses on nitrogen mustards; their discovery, mechanism
of action and their derivatives synthesized so far.
Results: Alkylation of DNA is held primarily responsible for cell death. DNA alkylators covalently bind
with DNA thereby inhibiting its natural processes and thus cause cell deaths. Various DNA alkyators, aziridines,
epoxides, methane sulfonates, nitrosoureas, methyl hydrazines, platinum complexes and most prominently
nitrogen mustards and its derivatives are extensively studied. Alkylation by nitrogen mustards proceeds
via the formation of aziridinium ion intermediate adopting SN1 or SN2 pathway depending on the type
of alkylating drugs. Ab-initio studies on isolated GC base pairs have confirmed that nitrogen mustard derivative
like chlorambucil attacks preferentially the N7 position of guanine. Also alkylation by nitrogen or sulphur
mustards is enthalpy driven (ΔH < 0) and spontaneous (ΔG < 0). Conjugation of melphalan, chlorambucil
and other nitrogen mustards to steroids, as well as conjugation of CNS active chromophore to nitrogen
mustards have led to designing new potent anti-cancer drugs.
Conclusion: The article extensively dwells in studies (both experimental and theoretical) on different DNA
interacting drugs, types of DNA alkylators focussing particularly on nitrogen mustards and fate of alkylated
DNA. Drug resistance and site specificity have been the major impediment in devising nitrogen mustard based
cancer therapy. Among several nitrogen mustard derivatives synthesized, tallimustine, distamycine have been
among the particularly successful derivatives in overcoming these limitations. Future studies on designing cell
specific anti cancer drugs based on nitrogen mustards are deemed essential.