Abstract
(+)-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.
| Original language | English |
|---|---|
| Pages (from-to) | 1060-1065 |
| Number of pages | 6 |
| Journal | ACS Medicinal Chemistry Letters |
| Volume | 8 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - Oct 12 2017 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Drug Discovery
- Organic Chemistry
Cite this
Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough. / Taguchi, Akihiro; Hamada, Keisuke; Shiozuka, Masataka; Kobayashi, Misaki; Murakami, Saori; Takayama, Kentaro; Taniguchi, Atsuhiko; Usui, Takeo; Matsuda, Ryoichi; Hayashi, Yoshio.
In: ACS Medicinal Chemistry Letters, Vol. 8, No. 10, 12.10.2017, p. 1060-1065.Research output: Contribution to journal › Article
}
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
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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UR - http://www.scopus.com/inward/citedby.url?scp=85031287831&partnerID=8YFLogxK
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 -