Design, synthesis, chemical and biological evaluation of brain targeted alkylating agent using reversible redox prodrug approach

The aim of the present work is to investigate the utility of redox chemical delivery prodrug approach for the targeted and sustained release of an alkylating anticancer agent in the brain. The N-methyl-1,4-dihydronicotinate ester of an alkylating nitrogen mustard NM-CDS (4) was synthesized in three step reactions. Structures of all the synthesized compounds were confirmed by UV, IR, (1H&13C) NMR and CHN elemental studies. In vitro chemical oxidation studies with silver nitrate of NM-CDS (4) indicated that it can be readily converted into its corresponding quaternary salt (3) with half life of 8 min. In vitro biological oxidation studies showed facile oxidation in biological media and rate of oxidation followed pseudo first-order kinetics with reasonable half-lives of 32.5 min in rat blood, 24.2 min in human blood and 19.4 min in brain homogenate. The in vivo studies on Sprague-Dawley rats were performed. The NM-CDS (4) at a dose of 40 mg/kg, was injected into rats. At selected time intervals, blood samples and the brains were collected and analyzed by UV spectrophotometer. The results demonstrated that NM-CDS (4) was able to cross the blood-brain barrier (BBB) at detectable concentration, oxidized to its active quaternary salt (Q-salt) (3) and sustained there for some period of time. The in silico ADME descriptors required for CNS activity were determined by computational, online (Molinspiration) and QikProp 3.2 software (Schrodinger, USA) that further indicated that NM-CDS (4) has a good potential to cross the BBB and show CNS antitumor activity.