Synthesis, Alkylation Activity and Physico-chemical Evaluation of Benzodiazepine Linked Nitrogen Mustard Agent to Penetrate the Blood-Brain Barrier

Abstract

The design of drugs for the chemotherapy of tumours of the central nervous system contains numerous challenges. Most of clinical alkylating anticancer agent, such as nitrogen mustard (mustine) is too polar to cross blood-brain barrier. So it is aimed to link nitrogen mustard to CNS active 1,4-benzodiazepine carrier to obtain CNS active benzodiazepine derivative of nitrogen mustard. The benzodiazepine-mustard agent was oily at room temperature and stable when stored at less than 0 ºC. Structures of all the synthesized compounds were confirmed by UV, IR and ¹H NMR spectroscopy. The in vitro chemical alkylation activity studies (NBP) of benzodiazepine-mustard was comparable to that of N,N-bis-(2-chloroethyl)amino moiety as standard alkylating agent. The log P value of benzo-mustard determined experimentally is significantly higher than nordiazepam. Value of polar surface area for the benzo-mustard agent (35.9 A²) predicts that > 90 % of any amount present in the intestinal tract will be absorbed. The study of some physico-chemical properties calculated by online software such as lipophilicity, log BB (0.295), no. of violation of Lipinski's rule of five (0), number of NH or OH hydrogen bond donors (0) and nON value (4) also indicates that it can be a potential candidate for targeted delivery of nitrogen mustard to the brain for the treatment of brain tumour.