Amphiphilic aminoglycosides with increased selectivity for inhibition of connexin 43 (Cx43) hemichannels.

Autor: Subedi YP; Department of Chemistry and Biochemistry, Utah State University, 0300, Old Main Hill, Logan, UT, 84322-0300, USA., Kjellgren A; Department of Cell Physiology and Molecular Biophysics, And Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, 79430-6551, USA., Roberts P; Department of Chemistry and Biochemistry, Utah State University, 0300, Old Main Hill, Logan, UT, 84322-0300, USA., Montgomery H; Department of Chemistry and Biochemistry, Utah State University, 0300, Old Main Hill, Logan, UT, 84322-0300, USA., Thackeray N; Department of Chemistry and Biochemistry, Utah State University, 0300, Old Main Hill, Logan, UT, 84322-0300, USA., Fiori MC; Department of Cell Physiology and Molecular Biophysics, And Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, 79430-6551, USA., Altenberg GA; Department of Cell Physiology and Molecular Biophysics, And Center for Membrane Protein Research, Texas Tech University Health Sciences Center, Lubbock, TX, 79430-6551, USA., Chang CT; Department of Chemistry and Biochemistry, Utah State University, 0300, Old Main Hill, Logan, UT, 84322-0300, USA. Electronic address: tom.chang@usu.edu.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Oct 01; Vol. 203, pp. 112602. Date of Electronic Publication: 2020 Jul 12.
DOI: 10.1016/j.ejmech.2020.112602
Abstrakt: Gap junction channels formed by the association of connexin hemichannels play a crucial role in intercellular communication. Connexin 43 (Cx43) is expressed in a variety of tissues and organs, including heart and brain, and abnormal sustained opening of undocked "free" hemichannels contributes to the cell damage in cardiac infarcts and stroke. Selective inhibitors of Cx43 hemichannels for clinical use are then desirable. Here, we synthesized and tested new aminoglycosides for their connexin inhibitory activity towards Cx26 and Cx43 hemichannels. The lead compounds displayed enhanced Cx43/Cx26 selectivity for hemichannel inhibition when compared to the parent kanamycin A and other commercially available aminoglycosides. These lead compounds are not cytotoxic to mammalian cells and show promise for the treatment of ischemic damage of the heart, brain, and kidneys. We identified a new compound as a promising lead based on its good selectivity for Cx43 hemichannels inhibition and the simplicity and affordability of its production.
Competing Interests: Declaration of competing interest There are no conflicts to declare.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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