title: Development of a novel sulfonate ester-based prodrug strategy.
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.
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Electronic address: hanaya-kn@pha.keio.ac.jp.
authors.forename: Kengo
authors.initials: K
authors.lastname: Hanaya
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Yoshioka
authors.affiliation: Center for Technologies against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ariyasu
authors.affiliation: Center for Technologies against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan; Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Aoki
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shoji
authors.affiliation: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugai
mesh_terms: D000333:Aeromonas / Q000201:enzymology*; D000476:Alkanesulfonates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002739:Chloroquinolinols / Q000008:administration & dosage / Q000378:metabolism*; D003500:Cyclization; D006801:Humans; D006868:Hydrolysis; D007930:Leucine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism*; D011437:Propylamines / Q000138:chemical synthesis / Q000378:metabolism; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D000476:Alkanesulfonates; D002739:Chloroquinolinols; D011355:Prodrugs; D011437:Propylamines; D013449:Sulfonamides; C519493:cloxyquin; D000626:Aminopeptidases; D007930:Leucine
keywords: Prodrug; Protease; Suicide substrate; Sulfonate; Sultam