Bh. Wang et al., SYNTHESIS OF A NOVEL ESTERASE-SENSITIVE CYCLIC PRODRUG SYSTEM FOR PEPTIDES THAT UTILIZES A TRIMETHYL LOCK-FACILATATED LACTONIZATION REACTION, Journal of organic chemistry, 62(5), 1997, pp. 1363-1367
This paper describes a unique strategy for preparing cyclic prodrugs o
f peptides that have increased metabolic stability and increased cell
membrane permeability when compared to the linear peptides. By taking
advantage of a unique ''trimethyl lock''-facilitated lactonization sys
tem, an esterase-sensitive cyclic prodrug of a model hexapeptide H-Trp
-Ala-Gly-Gly-Asp-Ala-OH was synthesized by linking the N-terminal amin
o group to the C-terminal carboxyl group. The key intermediate for bot
h approaches was compound 9 with Boc-Ala attached to the phenol hydrox
yl group of the ''trimethyl lock'' linker through an ester bond, which
can then be incorporated into the peptide using a normal coupling rea
gent for peptide synthesis. The synthesis of the linear peptides was a
ccomplished using both solution-phase and solid-phase approaches with
the solution-phase approach having the advantage of using the key inte
rmediate 9 most efficiently. Cyclization using standard high-dilution
techniques provided cyclic prodrug 13. In 90% human plasma, prodrug 13
released the original peptide, as designed, through an apparent ester
ase-catalyzed hydrolysis of the phenol ester bond.