Negamycin Analogue with Readthrough-Promoting Activity as a Potential Drug Candidate for Duchenne Muscular Dystrophy
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- 作者：Akihiro Taguchi ; Shigenobu Nishiguchi ; Masataka Shiozuka ; Takao Nomoto ; Mayuko Ina ; Shouta Nojima ; Ryoichi Matsuda ; Yoshiaki Nonomura ; Yoshiaki Kiso ; Yuri Yamazaki ; Fumika Yakushiji ; Yoshio Hayashi
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：February 9, 2012
- 年：2012
- 卷：3
- 期：2
- 页码：118-122
- 全文大小：277K
- 年卷期：v.3,no.2(February 9, 2012)
- ISSN：1948-5875
文摘
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鈥揳ctivity 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.