Bhabesh Chandra Deka and Pradip Kr. Bhattacharyya* Pages 10 - 46 ( 37 )
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.
Nitrogen mustards, DNA alkylator, chlorambucil, melphalan, bendamustine, uracil mustard.
Department of Chemistry, Arya Vidyapeeth College, Guwahati-781016 Assam, Department of chemistry, Arya Vidyapeeth College, Guwahati-781016 Assam