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Synthesis in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent

Abstract

Every year, there are more than two lakhs of population affected with CNS tumor. Nitrogen mustard class of alkylating drugs, used clinically against various types of tumor, is too polar to cross the BBB. The redox chemical drug delivery prodrug approach is one of the most interesting procedures for delivering drugs in a sustained and specific manner to the CNS. The objective of the present study is to investigate the redox drug delivery system for the delivery of bis(2-chloroethyl)amine (nor mustard) as alkylating cytotoxic agent to the brain. Various redox derivatives of CDS-M (4ad) were synthesized incorporating different alkyl/aryl moieties at ring nitrogen and subjected to in silico physicochemical parameters determination required for CNS activity through computational, online, and QikProp 3.2 software. The results of stability study, in vitro chemical (silver nitrate), and biological oxidation studies in human blood, rat blood, and brain homogenate for all CDS-M (4ad) have been promising and suggest that brain targeting could be possible with more stable CDS-M (4d). The in vivo study showed that CDS-M (4d) was able to cross the BBB at detectable concentrations, and in vitro NBP alkylating activity of its quaternary salt (3d) was comparable to the known drug chlorambucil among all the synthesized derivatives.

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Acknowledgments

Authors are thankful to College Managing Committee, SCOP, Nangal for providing necessary facilities to carry out research work. Authors wish to express their gratitude to Dr. Manoj Kumar, Professor of Pharmaceutical Chemistry, UIPS, Panjab University, Chandigarh to carry out ADME study at his lab. Authors are also thankful to SAIF, Panjab University, Chandigarh for cooperation in getting the spectral data.

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Correspondence to Rajesh K. Singh.

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Singh, R.K., Prasad, D.N. & Bhardwaj, T.R. Synthesis in vitro/in vivo evaluation and in silico physicochemical study of prodrug approach for brain targeting of alkylating agent. Med Chem Res 22, 5324–5336 (2013). https://doi.org/10.1007/s00044-013-0537-0

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Keywords

  • Alkylating agent
  • Chemical delivery system
  • In silico ADME
  • NBP assay
  • In vitro/in vivo studies