Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

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 (4a–d) 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 (4a–d) 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Al-Obaid AM, Farag HA, Khalil AA et al (2006) Synthesis and investigation of novel shelf-stable, brain-specific chemical delivery system. Saudi Pharm J 14(1):1–15

    CAS  Google Scholar 

  • Balazs MK, Anderson A, Iwamoto RH, Lim P (1970) Synthesis of 4-{p-((2-chloroethyl)-(2-hydroxyethyl)amino)phenyl}butyric acid and its behaviours in the 4-(4-nitrobenzyl)pyridine assay procedure. J Pharm Sci 59(4):563–565

    Article  CAS  PubMed  Google Scholar 

  • Bartzatt RL (2004) Synthesis and alkylating activity of a nitrogen mustard agent to penetrate the blood–brain barrier. Drug Deliv 11:19–26

    Article  CAS  PubMed  Google Scholar 

  • Bodor N, Farag H (1983) Improved delivery through biological membrane. XI. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine. J Med Chem 26:318–328

    Article  CAS  PubMed  Google Scholar 

  • Bodor N, Farag HH, Brewster ME (1981) Site-specific sustained release of drugs to the brain. Science 214:1370–1372

    Article  CAS  PubMed  Google Scholar 

  • Bodor N, Venkatraghavan V, Windwood D, Estes K, Brewster E (1989) Improved delivery through biological membranes. XLI. Brain-enhanced delivery of chlorambucil. Int J Pharm 53:195–208

    Article  CAS  Google Scholar 

  • Clark D (1999) Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood brain barrier penetration. J Pharm Sci 8(88):815–821

    Article  Google Scholar 

  • Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumours diagnosed in the United States in 2005–2009. Neuro-Oncology 14(5):1–49

    Article  Google Scholar 

  • El-Sherbeny MA, Al-Salem HS, Sultan MA, Radwan MA, Farag HA, Ei-Subbagh HI (2003) Synthesis in vitro & in vivo evaluation of a delivery system for targeting anticancer drug to brain. Arch Pharm 336(10):445–455

    Article  CAS  Google Scholar 

  • Francisco AP, Perry MJ, Moreira R, Mendes E (2008). Alkylating agents, Chap 9. In: Misssailidis S (ed) Anticancer therapeutics. Wiley, Weinheim, p 133–158

  • Genka S, Deutsch J, Shetty UH, Stahle PL, John V, Lieberburg IM, Ali-Osman F, Rapoport SI, Greig NH (1993) Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil. Clin Exp Metastasis 11:131–140

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Bombrelli R, Gonzalez-Perez M, Calle E, Casado J (2012) Potential of the NBP method for the study of alkylation mechanism: NBP as a DNA-model. Chem Res Toxicol 25:1175–1191

    Google Scholar 

  • Hirata T, Driscoll JS (1976) Potential CNS antitumor agents-phenothiazines I: nitrogen mustard derivatives. J Med Chem 65:1699–1701

    CAS  Google Scholar 

  • Jorgensen WL (2009) Efficient drug lead discovery and optimization. Acc Chem Res 42(6):724–733

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kapuriya N, Kakadiya R, Dong H, Kumar A, Lee P-C, Zhang X, Chou T-C, Lee T-C, Chen C-H, Lam K, Marvania B, Shah e A, Su T-L (2011) Design, synthesis, and biological evaluation of novel water-soluble N-mustards as potential anticancer agents. Bioorg Med Chem 19:471–485

    Google Scholar 

  • Kelder J, Grootenhuis P, Bayada D, Delbressine L, Ploemen J (1999) Polar molecular surface at a dominating determinant for oral absorption and brain penetration of drugs. Pharm Res 10(16):1514–1519

    Article  Google Scholar 

  • Li Z, CaulfieldT QiuY, Copland JA, Tun HW (2012) Pharmacokinetics of bendamustine in the central nervous system: chemoinformatic screening followed by validation in a murine model. Med Chem Commun 3:1526–1530

    Article  CAS  Google Scholar 

  • Lipinski C, Lombardo F, Dominy B, Feeney P (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23:3–25

    Article  CAS  Google Scholar 

  • Mahmoud S, Mohammad A (2010) Brain-specific delivery of naproxen using different carrier systems. Arch Pharm Chem Life Sci 10:639–647

    Article  Google Scholar 

  • Molinspiration Cheminformatics, Bratislava, Slovak Republic. Available online http://www.molinspiration.com/services/properties.html. Accessed 22 April 2010

  • Mourelatos C, Kareli D, Dafa E, Argyraki M, Koutsourea A, Papakonstantinou I, Fousteris M, Pairas G, Nikolaropoulos S, Lialiaris TS (2012) Cytogenetic and antineoplastic effects by newly synthesised steroidal alkylators in lymphocytic leukaemia P388 cells in vivo. Mut Res 7:1–6

    Article  Google Scholar 

  • Palm K, Luthman K, Ungell A, Strandluno G, Artusson P (1996) Correlation of drug absorption with molecular surface properties. J Pharm Sci 1(85):32–39

    Article  Google Scholar 

  • Peng GW, Marquez VE, Driscoll JS (1975) Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 18(8):846–849

    Article  CAS  PubMed  Google Scholar 

  • Phelan MJ, Bodor N (1989) Improved delivery through biological membranes. XXXVII. Synthesis and stability of novel redox derivatives of naproxen and indomethacin. Pharm Res 6(8):667–676

    Article  CAS  PubMed  Google Scholar 

  • Pop E, Loftsson T, Bodor N (1991) Solubilization and stabilization of benzylpencillin chemical delivery system by 2-hydroxypropyl-β-cyclodextrin. Pharm Res 8:1044–1049

    Article  CAS  PubMed  Google Scholar 

  • Prokai L, Prokai-Tatrai K, Bodor N (2000) Targeting drug to the brain by redox chemical drug delivery system. Med Res Rev 20:367–416

    Article  CAS  PubMed  Google Scholar 

  • Raghavan KS, Shek E, Bodor N (1987) Improved delivery through biological membranes. XXX. Synthesis and biological aspects of a 1,4-dihydropyridine based chemical delivery system for brain-sustained delivery of hydroxy CCNU. Anticancer Drug Des 2(1):25–36

    CAS  PubMed  Google Scholar 

  • Scutaru AM, Wenzel M, Gust R (2011) Bivalent bendamustine and melphalan derivatives as anticancer agents. Eur J Med Chem 46:1604–1615

    Article  CAS  PubMed  Google Scholar 

  • Sheha M, Al-Tayeb A, EI-Sherief H, Farag H (2003) New carrier for specific delivery to drugs to the brain. Bio Med Chem 11:1865–1872

    Article  CAS  Google Scholar 

  • Singh RK, Devi S, Prasad DN (2011) Synthesis, physicochemical and biological evaluation of CNS active 2-aminobenzophenone derivatives as potent skeletal muscle relaxant. Arab J Chem (in press) doi:10.1016/j.arabjc.2011.11.013

  • Singh RK, Prasad DN, Bhardwaj TR (2012a) Synthesis, alkylation activity and physicochemical evaluation of benzodiazpine-linked nitrogen mustard agent to penetrate the blood-brain barrier. Asian J Chem 24(12):5605–5608

    CAS  Google Scholar 

  • Singh RK, Sharma S, Malik S, Sharma D, Prasad DN, Bhardwaj TR (2012b) Synthesis and study of chemical delivery system for targeting nitrogen mustard to the brain. Asian J Chem 24(12):5635–5638

    CAS  Google Scholar 

  • Singh RK, Prasad DN, Bhardwaj TR (2012c) Synthesis, physicochemical properties and kinetic study of bis(2-chloroethyl)amine as cytotoxic agent for brain delivery. Arab J Chem (in press) doi:10.1016/j.arabjc.2012.11.005

  • Stout DM, Meyers AI (1982) Recent advances in the chemistry of dihyropyridines. Chem Rev 82:223–243

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Pharmaceutical Chemistry Division, Shivalik College of Pharmacy, Nangal, Rupnagar, 140126, Punjab, India

    Rajesh K. Singh & D. N. Prasad

  2. Indo-Soviet Friendship College of Pharmacy, Moga, 142001, Punjab, India

    T. R. Bhardwaj

Authors
  1. Rajesh K. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. N. Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. R. Bhardwaj
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rajesh K. Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0537-0

Keywords

Search

Navigation