Synthesis of a novel esterase-sensitive cyclic prodrug of a hexapeptide using an (acyloxy)alkoxy promoiety
Document Type
Article
Publication Title
Journal of Organic Chemistry
Abstract
Synthetic methodology for preparing novel esterase-sensitive cyclic prodrugs of peptides with increased protease stability and cell membrane permeability compared to linear peptides is described. Cyclic prodrug 1 of the hexapeptide H-Trp-Ala-Gly-Gly-Asp-Ala-OH linked by the N-terminal amino group to the C-terminal carboxyl group via an (acyloxy)alkoxy promoiety was synthesized. A convergent synthetic approach involving Boc[[(alaninyloxy)methyl]carbonyl]-N-tryptophan (2) and H-Ala-Gly-Gly-Asp(OBzl)-OTce (3) was used. The key fragment 2 has the promoiety inserted between the Ala and the Trp residues. Fragment 3 was synthesized by a solution-phase approach using standard Boc-amino acid chemistry. These fragments were coupled to produce the protected linear hexapeptide, which after deprotection was cyclized using standard high-dilution techniques to yield cyclic prodrug 1. In pH 7.4 buffer (HBSS) at 37°C, cyclic prodrug 1 was shown to degrade quantitatively to the hexapeptide (t( 1/4 ) = 206 ± 11 min). The rate of hydrolysis of cyclic prodrug 1 was significantly faster in human blood (t( 1/4 ) = 132 ± 4 min) than in HBSS. Paraoxon, a known inhibitor of esterases, slowed this hydrolysis of cyclic prodrug 1 to a value (t( 1/4 ) = 198 ± 9 min) comparable to the chemical stability. In human blood, cyclic prodrug 1 was shown to be 25-fold more stable than the linear hexapeptide.
First Page
1356
Last Page
1362
DOI
10.1021/jo961696a
Publication Date
1-1-1997
Recommended Citation
Gangwar, Sanjeev; Pauletti, Giovanni M.; Siahaan, Teruna J.; Stella, Valentino J.; and Borchardt, Ronald T., "Synthesis of a novel esterase-sensitive cyclic prodrug of a hexapeptide using an (acyloxy)alkoxy promoiety" (1997). Pharmaceutical and Administrative Sciences Faculty Publications. 204.
https://doi.org/10.1021/jo961696a
https://collections.uhsp.edu/pharm-admin-sciences_pubs/204