| Autor: |
Maianti JP; Department of Chemistry, Université de Montréal , CP 6128 Succ. Centre-Ville, Montréal, Québec H3C3J7, Canada., Kanazawa H, Dozzo P, Matias RD, Feeney LA, Armstrong ES, Hildebrandt DJ, Kane TR, Gliedt MJ, Goldblum AA, Linsell MS, Aggen JB, Kondo J, Hanessian S |
| Jazyk: |
angličtina |
| Zdroj: |
ACS chemical biology [ACS Chem Biol] 2014 Sep 19; Vol. 9 (9), pp. 2067-73. Date of Electronic Publication: 2014 Jul 14. |
| DOI: |
10.1021/cb5003416 |
| Abstrakt: |
Aminoglycoside antibiotics are pseudosaccharides decorated with ammonium groups that are critical for their potent broad-spectrum antibacterial activity. Despite over three decades of speculation whether or not modulation of pKa is a viable strategy to curtail aminoglycoside kidney toxicity, there is a lack of methods to systematically probe amine-RNA interactions and resultant cytotoxicity trends. This study reports the first series of potent aminoglycoside antibiotics harboring fluorinated N1-hydroxyaminobutyryl acyl (HABA) appendages for which fluorine-RNA contacts are revealed through an X-ray cocrystal structure within the RNA A-site. Cytotoxicity in kidney-derived cells was significantly reduced for the derivative featuring our novel β,β-difluoro-HABA group, which masks one net charge by lowering the pKa without compromising antibacterial potency. This novel side-chain assists in evasion of aminoglycoside-modifying enzymes, and it can be easily transferred to impart these properties onto any number of novel analogs. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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