O-N intramolecular acyl migration reaction in the development of prodrugs and the synthesis of difficult sequence‐containing bioactive peptides

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Abstract
NOintramolecular acyl migration in Ser- or Thr-containing peptides is a well-known side reaction in peptide chemistry. It results in the mutual conversion of ester and amide bonds. Our medicinal chemistry study focused on the fact that the O-acyl product can be readily converted to the original N-acyl form under neutral or slightly basic conditions in an aqueous buffer and the liberated ionized amino group enhances the water solubility of O-acyl products. Because of this, we have developed a novel class of “ON intramolecular acyl migration”-type water-soluble prodrugs of HIV-1 protease inhibitors. These prodrugs released the parent drugs via a simple chemical mechanism with no side reaction. In this study, we applied this strategy to important cancer chemotherapeutic agents, paclitaxel and its derivatives, to develop water-soluble taxoid prodrugs, and found that these prodrugs, 2′-O-isoform of taxoids, showed promising results with higher water solubility and proper kinetics in their parent drug formation by a simple pH-dependent chemical mechanism with ON intramolecular acyl migration. These results suggest that this strategy would be useful in toxicology and medical economics. After the successful application of ON intramolecular acyl migration in medicinal chemistry, this concept was recently used in peptide chemistry for the synthesis of “difficult sequence-containing peptides.” The strategy was based on hydrophilic O-acyl isopeptide synthesis followed by the ON intramolecular acyl migration reaction, leading to the desired peptide. In a model study with small, difficult sequence-containing peptides, synthesized “O-acyl isopeptides” not only improved the solubility in various media and efficiently performed the high performance liquid chromatography purification, but also altered the nature of the difficult sequence during SPPS, resulting in the efficient synthesis of O-acyl isopeptides with no complications. The subsequent ON intramolecular acyl migration of purified O-acyl isopeptides afforded the desired peptides as precipitates with high yield and purity. Further study of the synthesis of a larger difficult sequence-containing peptide, Alzheimer's disease-related peptide (Aβ1–42), surprisingly showed that only one insertion of the O-acyl group drastically improved the unfavorable nature of the difficult sequence in Aβ1–42, and achieved efficient synthesis of 26-O-acyl isoAβ1–42 and subsequent complete conversion to Aβ1–42 via the ON intramolecular acyl migration reaction of 26-O-acyl isoAβ1–42. This suggests that our new method based on ON intramolecular acyl migration is an important method for the synthesis of difficult sequence-containing bioactive peptides. © 2004 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2004

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