Reversible redox system-based drug design, synthesis, and evaluation for targeting nitrogen mustard across brain

Abstract

Target drug delivery of nitrogen mustard anticancer agents for a brain tumor is still a challenge due to their high hydrophilicity, poor physicochemical properties, and toxicity to normal tissues. The present study is, therefore, an attempt to investigate the possibility of improving the targeting potential and sustained release of nitrogen mustard alkylating agent to brain by employing reversible redox chemical delivery system approach. Various redox derivatives CDS-L-M (4a–c) based on dihydropyridine ↔ quaternary pyridinium ion redox system were synthesized and characterized by IR, (1H and 13C)-NMR, and CHN elemental studies. The potential of these CDS derivatives (4a–c) to penetrate the blood–brain barrier was computed through an online software program and the values analyzed lay between the ranges those are required for good brain penetration. The results of storage stability study, in vitro chemical oxidation (silver nitrate) and pharmacokinetic studies in human blood, rat blood and brain homogenate for all CDS-L-M (4a–c) demonstrated that all derivatives could be oxidized into corresponding quaternary salts at an adequate rate, which suggested that brain targeting could be possible with more stable CDS-L-M (4c). The in vivo study on rats showed that administration of the CDS-L-M (4c) resulted in the sustained level of the corresponding salt (3c) in the brain, while blood levels of the oxidized metabolite rapidly fell. The in vitro NBP alkylating activity of quaternary salt (3c) of CDS-L-M (4c) was comparable to the known drug chlorambucil among all the synthesized derivatives.