Synthesis and use of sulfonamide-, sulfoxide-, or sulfone-containing aminoglycoside-CoA bisubstrates as mechanistic probes for aminoglycoside N-6'-acetyltransferase.
Aminoglycoside-coenzyme A conjugates are challenging synthetic targets because of the wealth of functional groups and high polarity of the starting materials. We previously reported a one-pot synthesis of amide-linked aminoglycoside-CoA bisubstrates. These molecules are nanomolar inhibitors of aminoglycoside N-6'-acetyltransferase Ii (AAC(6')-Ii), an important enzyme involved in bacterial resistance to aminoglycoside antibiotics. We report here the synthesis and biological activity of five new aminoglycoside-CoA bisubstrates containing sulfonamide, sulfoxide, or sulfone groups. Interestingly, the sulfonamide-linked bisubstrate, which was expected to best mimic the tetrahedral intermediate, does not show improved inhibition when compared with amide-linked bisubstrates. On the other hand, most of the sulfone- and sulfoxide-containing bisubstrates prepared are nanomolar inhibitors of AAC(6')-Ii.
Gao
Feng
F
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montréal, Québec, Canada H3A 2K6.
Yan
Xuxu
X
Zahr
Omar
O
Larsen
Aaron
A
Vong
Kenward
K
Auclair
Karine
K
D000123:Acetyltransferases / Q000737:chemistry* / Q000378:metabolism; D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003065:Coenzyme A / Q000737:chemistry; D015195:Drug Design; D008956:Models, Chemical; D008968:Molecular Conformation; D016877:Oxidants / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D012995:Solubility; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000494:pharmacology; D014867:Water / Q000737:chemistry
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016877:Oxidants; D013449:Sulfonamides; D013450:Sulfones; D013454:Sulfoxides; D014867:Water; D000123:Acetyltransferases; C056532:aminoglycoside N(6')-acetyltransferase; D010100:Oxygen; D003065:Coenzyme A