Design, synthesis and in vitro cytotoxicity study of benzodiazepine-mustard conjugates as potential brain anticancer agents

Abstract The combination of two pharmacological entities in a single compound has been utilized as a promising drug design strategy for site-specificity. So two nitrogen mustard agents were synthesized by conjugating mustard with the benzodiazepine nucleus in the hope to obtain central nervous system (CNS) antitumor agents. The benzodiazepine part is aimed to serve as a CNS active carrier enabling the alkylating moiety to cross the BBB by altering its physicochemical properties. Structures of all the synthesized compounds were confirmed by IR, NMR ( 1 H & 13 C), mass spectral and elemental studies. The benzodiazepine-mustard conjugates are oily at room temperature and quite stable when stored in refrigerator for 2 months. Both compounds when evaluated for NBP alkylating activity against chlorambucil, proved to be active alkylating agents. The compounds were markedly active when subjected to in vitro biological evaluation using an MTT colorimetric assay against four human cancer cell lines (A-549, COLO 205, U-87 MG and IMR-32). The physicochemical ADME studies were also analyzed using Qikprop 2.5 tools of Schodinger software which further indicates that both compounds can be potential candidates for the treatment of brain tumor.