Development of a novel sulfonate ester-based prodrug strategy

Kengo Hanaya; Shohei Yoshioka; Shinya Ariyasu; Shin Aoki; Mitsuru Shoji; Takeshi Sugai

doi:10.1016/j.bmcl.2015.11.074

Development of a novel sulfonate ester-based prodrug strategy

Kengo Hanaya, Shohei Yoshioka, Shinya Ariyasu, Shin Aoki, Mitsuru Shoji, Takeshi Sugai

School of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

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.

Original language	English
Pages (from-to)	545-550
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	2
DOIs	https://doi.org/10.1016/j.bmcl.2015.11.074
Publication status	Published - 2016 Jan 15

Keywords

Prodrug
Protease
Suicide substrate
Sulfonate
Sultam

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2015.11.074

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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.",

keywords = "Prodrug, Protease, Suicide substrate, Sulfonate, Sultam",

author = "Kengo Hanaya and Shohei Yoshioka and Shinya Ariyasu and Shin Aoki and Mitsuru Shoji and Takeshi Sugai",

note = "Funding Information: This study is supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science (MEXT) and Japan Agency for Medical Research and development (AMED) and Keio Gijuku Academic Development Funds. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

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doi = "10.1016/j.bmcl.2015.11.074",

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AU - Hanaya, Kengo

AU - Yoshioka, Shohei

AU - Ariyasu, Shinya

AU - Aoki, Shin

AU - Shoji, Mitsuru

AU - Sugai, Takeshi

N1 - Funding Information: This study is supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science (MEXT) and Japan Agency for Medical Research and development (AMED) and Keio Gijuku Academic Development Funds. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2016/1/15

Y1 - 2016/1/15

N2 - 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.

AB - 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.

KW - Prodrug

KW - Protease

KW - Suicide substrate

KW - Sulfonate

KW - Sultam

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Development of a novel sulfonate ester-based prodrug strategy

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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