TY - JOUR
T1 - Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough
AU - Taguchi, Akihiro
AU - Hamada, Keisuke
AU - Shiozuka, Masataka
AU - Kobayashi, Misaki
AU - Murakami, Saori
AU - Takayama, Kentaro
AU - Taniguchi, Atsuhiko
AU - Usui, Takeo
AU - Matsuda, Ryoichi
AU - Hayashi, Yoshio
N1 - Funding Information:
The authors thank Dr. Ced́ ric Rentier, Tokyo University of Pharmacy and Life Sciences, for proofreading the manuscript and improvement suggestions, as well as Mr. Masaya Kotake and Ms. Noriko Omura, Tokyo University of Pharmacy and Life Sciences for the technical assistance and Dr. Yamato Kikkawa, Tokyo University of Pharmacy and Life Sciences, for kindly providing us with the human dermal fibroblast cell line. This work was supported by the Japan Society for the Promotion of Science (JSPS), KAKENHI including a Grant-in-Aid for JSPS Research Fellow 16J08454, a Grant-in-Aid for Scientific Research (B) 23390029, a Grant-in-Aid for Young Scientists (B) 25860092, a Grant-in-Aid for Research Activity Start-up 25893258, and a Grant-in-Aid for Scientific Research on Innovative Areas “Chemical Biology of Natural Products” from the Ministry of Education, Culture, Sports, Science and Technology, and Platform for Drug Discovery, Informatics and Structural Life Science, and Intramural Research Grant (29-4) for Neurological and Psychiatric Disorders of NCNP. MEXT-supported Program for the Strategic Research Foundation at Private Universities.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/10/12
Y1 - 2017/10/12
N2 - (+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure-activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.
AB - (+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure-activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.
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U2 - 10.1021/acsmedchemlett.7b00269
DO - 10.1021/acsmedchemlett.7b00269
M3 - Article
AN - SCOPUS:85031287831
VL - 8
SP - 1060
EP - 1065
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 10
ER -