title: Negamycin analogue with readthrough-promoting activity as a potential drug candidate for duchenne muscular dystrophy.
abstract: A series of (+)-negamycin 1 analogues were synthesized, and their readthrough-promoting activity was evaluated for nonsense mutations in Duchenne muscular dystrophy (DMD). A structure-activity relationship study indicated that 11b was the most potent drug candidate. Immunohistochemical analyses suggested that treatment with 11b restored dystrophin expression in mdx mice, a DMD mouse model. Furthermore, 11b decreased serum creatine kinase (CK) levels, an indicator of muscle fiber destruction. Most importantly, 11b demonstrated lower toxicity than 1, and thus, it could be a useful candidate for long-term treatment of DMD.
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Shigenobu
authors.initials: S
authors.lastname: Nishiguchi
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo , Komaba, Tokyo 153-8902, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Shiozuka
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Nomoto
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Ina
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Shouta
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo , Komaba, Tokyo 153-8902, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Matsuda
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo , Komaba, Tokyo 153-8902, Japan ; Institute of Microbial Chemistry , Shinagawa-ku, Tokyo 141-0021, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nonomura
authors.affiliation: Department of Medicinal Chemistry, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yamazaki
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Fumika
authors.initials: F
authors.lastname: Yakushiji
authors.affiliation: Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , Hachioji, Tokyo 192-0392, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hayashi
keywords: Duchenne muscular dystrophy; Negamycin; genetic disease; hydrazino dipeptide; nonsense mutations; readthrough-promoting activity