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Synthesis of an Esterase-Sensitive Cyclic Prodrug of a Model Hexapeptide Having Enhanced Membrane Permeability and Enzymatic Stability Using a 3-(2′-Hydroxy-4′,6′-Dimethylphenyl)-3,3-Dimethyl Propionic Acid Promoiety

  • Binghe Wang
  • Sanjeev Gangwar
  • Giovanni Pauletti
  • Teruna Siahaan
  • Ronald T. Borchardt
Part of the Methods in Molecular Medicine™ book series (MIMM, volume 23)

Abstract

One of the major obstacles to the development of biologically active peptides as clinically useful therapeutic agents has been their low permeation through biological barriers (e.g., intestinal mucosa, blood-brain barrier) and their metabolic lability (1,2). Overcoming these problems is a very contemporary issue for the development of peptide pharmaceuticals. In the preceding chapter, we have indicated that masking the C- and N-terminal polar functional groups of a peptide through cyclization with an acyloxyalkoxy linker can greatly enhance the membrane permeation and metabolic stability of the linear peptide (3). In this chapter, we wish to report a method for the preparation of esterase-sensitive cyclic prodrugs of peptides by taking advantage of a unique “trimethyl lock”-facilitated lactonization system (Fig. 1). Substituted phenol propionic acid derivatives such as 2, upon unmasking of the hydroxyl group, undergo a facile spontaneous intramolecular cyclization to release the moieties attached to the carboxyl functional group (Fig. 1) (4, 5, 6). The facile cyclization reaction is the result of the “trimethyl lock”, which was shown earlier to increase the rate of the cyclization reaction in the order of 105–7 (4, 5, 6, 7). The result of such facilitation is that compound 2 has a half-life of only approximately 100 s at room temperature in aqueous solution (8,9). Such systems have been used to develop prodrugs of amines and alcohols (8, 9, 10) and redox-sensitive protecting groups of amines (11).
Fig. 1.

The design of an esterase sensitive prodrug system for the cyclic deriva-tization of peptides.

Keywords

High Performance Liquid Chromatography Cyclic Peptide Linear Peptide Solid Phase Peptide Synthesis Sodium Hydrogen Carbonate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Humana Press Inc., Totowa, NJ 1999

Authors and Affiliations

  • Binghe Wang
    • 1
  • Sanjeev Gangwar
    • 1
  • Giovanni Pauletti
    • 1
  • Teruna Siahaan
    • 1
  • Ronald T. Borchardt
    • 1
  1. 1.Department of Pharmaceutical ChemistryThe University of KansasLawrence

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