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Development of Conformationally Restricted Negamycin Derivatives for Potent Readthrough Activity.

Noriko OmuraAkihiro TaguchiTomoki KuwaharaKeisuke HamadaMizuki WatanabeMasanori NakakukiSho KonnoKentaro TakayamaAtsuhiko TaniguchiToshifumi NomuraSatoshi ShutoYoshio Hayashi
Published in: ACS medicinal chemistry letters (2023)
(+)-Negamycin, which is a dipeptide-like antibiotic containing a hydrazide structure, exhibits readthrough activity, resulting in the restoration of dystrophin in the mdx mouse model of Duchenne muscular dystrophy (DMD). In our previous structure-activity relationship study of negamycin, we found that its natural analogue 3- epi -deoxynegamycin (TCP-107), without antimicrobial activity, showed a higher readthrough activity than negamycin. In this study, we designed and synthesized cyclopropane-based conformationally restricted derivatives of TCP-107 and evaluated their readthrough activity in the cell-based reporter assay against a TGA-type mutation derived from DMD. As a result, a down- cis isomer, TCP-304, showed significant readthrough activity among the four isomers. Moreover, TCP-306, a derivative acylated by l-α-aminoundecanoic acid, possessed approximately 3 times higher activity than TCP-304. These down- cis derivatives showed dose-dependent readthrough activity and were effective for not only TGA but also TAG mutations. These results suggest that the conformational restriction of negamycin derivatives by the introduction of the cyclopropane ring is effective for an exhibition of potent readthrough activity.
Keyphrases
  • duchenne muscular dystrophy
  • mouse model
  • structure activity relationship
  • high throughput
  • muscular dystrophy
  • bone marrow