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.
This is a preview of subscription content, log in via an institution to check access.
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
Balazs MK, Anderson A, Iwamoto RH, Lim P (1970) Synthesis of 4-{p-[(2-chloroethyl)-(2-hydroxyethyl)amino]phenyl}butyric acid and its behaviors in the 4-(4-nitrobenzyl) pyridine assay procedure. J Pharm Sci 59(4):563–565
Bartzatt RL (2004) Synthesis and alkylating activity of a nitrogen mustard agent to penetrate the blood–brain barrier. Drug Deliv 11:19–26
Bodor N, Farag H (1983) Improved delivery through biological membranes. XI. A redox chemical drug-delivery system and its use for brain-specific delivery of phenylethylamine. J Med Chem 26:315–318
Bodor N, Farag HH, Brewster ME (1981) Site-specific sustained release of drugs to the brain. Science 214:1370–1372
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
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
Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-Oncology 14(5):1–49
El-Sherbeny MA, Al-Salem HS, Sultan MA, Radwan MA, Farag HA, EI-Subbagh HI (2003) Synthesis in vitro and in vivo evaluation of a delivery system for targeting anticancer drug to the brain. Arch Pharm 336(10):445–455
Francisco AP, Perry MJ, Moreira R, Mendes E (2008) Alkylating agents. In: Misssailidis S (ed) Anticancer therapeutics, Chap 9. Wiley, New York, pp 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
Hirata T, Driscoll JS (1976) Potential CNS antitumor agents-phenothiazines I: nitrogen mustard derivatives. J Med Chem 65:1699–1701
Huttunen KM, Rautio J (2011) Prodrugs: an efficient way to breech delivery and targeting barriers. Curr Top Med Chem 11(2265):2287
Jorgensen WL (2009) Efficient drug lead discovery and optimization. Acc Chem Res 42(6):724–733
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
Leeson PD, Davis AM (2004) Time-related differences in the physical property profiles of oral drugs. J Med Chem 47:6338–6348
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 Deliv Rev 23:3–25
Molinspiration Cheminformatics (2012) Molinspiration Cheminformatics, Bratislava, Slovak Republic. http://www.molinspiration.com/services/properties.html. Accessed 20 April 2012
Osterberg T, Norinder U (2000) Prediction of polar surface area and drug transport processes using simple parameters and PLS statistics. J Chem Inf Comput Sci 40:1408–1411
Pajouhesh H, Lenz GR (2005) Medicinal chemistry properties of successful central nervous system drugs. NeuroRx 2:541–553
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
Pavan B, Dalpiaz A, Ciliberti N, Biondi C, Manfredini S, Vertuani S (2008) Progress in drug delivery to the central nervous system by the prodrug approach. Molecules 13:1035–1065
Peng GW, Marquez VE, Driscoll JS (1975) Potential central nervous system antitumor agents. Hydantoin derivatives. J Med Chem 18(8):846–849
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
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
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
Sheha M, Al-Tayeb A, EI-Sherief H, Farag H (2003) New carrier for specific delivery of drugs to the brain. Bio Med Chem 11:1865–1872
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. doi:10.1016/j.arabjc.2011.11.013
Singh RK, Sharma S, Malik S, Sharma D, Prasad DN, Bhardwaj TR (2012a) Synthesis and study of chemical delivery system for targeting nitrogen mustard to the brain. Asian J Chem 24(12):5635–5638
Singh RK, Prasad DN, Bhardwaj TR (2012b) Synthesis, physicochemical properties and kinetic study of bias (2-chloroethyl) amine as a cytotoxic agent for brain delivery. Arab J Chem. doi:10.1016/j.arabjc.2012.11.005
Singh RK, Prasad DN, Bhardwaj TR (2012c) Synthesis, alkylation activity and physicochemical evaluation of benzodiazepine-linked nitrogen mustard agent to penetrate the blood–brain barrier. Asian J Chem 24(12):5605–5608
Singh RK, Prasad DN, Bhardwaj TR (2013a) Synthesis, in vitro/in vivo evaluation and insilico physicochemical study of the prodrug approach for brain targeting of alkylating agent. Med Chem Res 22:5324–5336
Singh RK, Prasad DN, Bhardwaj TR (2013b) Design, synthesis and evaluation of aminobenzophenone derivatives containing nitrogen mustard moiety as potential CNS antitumor agents. Med Chem Res. doi:10.1007/s00044-013-0582-8
Stella VJ, Borchardt RT, Hageman MJ, Oliyai R, Maag H, Tilley JW (2007) Prodrugs: challenges and rewards part 1 and 2. Springer Science + Business Media, New York
Stout DM, Meyers AI (1982) Recent advances in the chemistry of dihyropyridines. Chem Rev 82:223–243
Sziraki I, Horvath K, Bodor N (2006) Comparative evaluation of estredox, a brain-targeted estradiol delivery system versus traditional estrogen replacement therapy. Pharmazie 61:140–143
Tapfer MK, Sebestyen L, Kurucz I, Horvath K, Szelenyi I, Bodor N (2004) New evidence for the selective, long-lasting central effects of the brain-targeted estradiol, estredox. Pharmacol Biochem Behav 77:423–429
Van de Waterbeemd H, Camenish G, Folkers G, Chretien JR, Raevsky OA (1998) Estimation of blood–brain barrier crossing of drugs using molecular size and shape, and H-bonding characteristic. J Drug Targets 6:151–165
Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, Hidalgo IJ (2005) Evaluation of the MDR–MDCK cell line as a permeability screen for the blood–brain barrier. Int J Pharm 288:349–359
Acknowledgments
Authors are thankful to the College Managing Committee, SCOP, Nangal for providing necessary facilities to carry out research work. The authors wish to express their gratitude to Dr. Manoj Kumar, Professor of Pharmaceutical Chemistry, UIPS, Panjab University, Chandigarh to carry out an 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
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Singh, R.K., Kumar, S., Prasad, D.N. et al. Reversible redox system-based drug design, synthesis, and evaluation for targeting nitrogen mustard across brain. Med Chem Res 23, 2405–2416 (2014). https://doi.org/10.1007/s00044-013-0833-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-013-0833-8