Development of a novel sulfonate ester-based prodrug strategy. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Hanaya, Kengo; Yoshioka, Shohei; Ariyasu, Shinya; Aoki, Shin; Shoji, Mitsuru; Sugai, Takeshi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 2(2016)
• Page Start: 545
• Page End: 550
• Publication Date: 2016-01-15
• Subjects: Sulfonate -- Prodrug -- Suicide substrate -- Protease -- Sultam; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.11.074
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A self-immolative γ-aminopropylsulfonate linker was investigated for use in the development of prodrugs that are reactive to various chemical or biological stimuli. To demonstrate their utility, a leucine-conjugated prodrug of 5-chloroquinolin-8-ol (5-Cl-8-HQ), which is a potent inhibitor against aminopeptidase from Aeromonas proteolytica (AAP), was synthesized. The sulfonate prodrug was considerably stable under physiological conditions, with only enzyme-mediated hydrolysis of leucine triggering the subsequent intramolecular cyclization to simultaneously release 5-Cl-8-HQ and form γ-sultam. It was also confirmed that this γ-aminopropylsulfonate linker was applicable for prodrugs of not only 8-HQ derivatives but also other drugs bearing a phenolic hydroxy group.