title: 5'-(N-aminoacyl)-sulfonamido-5'-deoxyadenosine: attempts for a stable alternative for aminoacyl-sulfamoyl adenosines as aaRS inhibitors.
abstract: Synthesis of aminoacyl-sulfamoyl adenosines (aaSAs) and their peptidyl conjugates as aminoacyl tRNA synthetase (aaRS) inhibitors remains problematic due to the low yield of the aminoacylation and the subsequent conjugation reaction causing concomitant formation of a cyclic adenosine derivative. In an effort to reduce this undesirable side reaction, we aimed to prepare the corresponding aminoacyl sulfonamide (aaSoA) analogues as more stable alternatives for aaSA derivatives. Deletion of the 5'-oxygen in aaSA analogues should render the C-5' less electrophilic and therefore improve the stability of the aminoacyl sulfamate analogues. We therefore synthesized six sulfonamides and compared their activity against the respective aaSA analogues. However, except for the aspartyl derivative, the new compounds are not able to inhibit the corresponding aaRS. Possible reasons for this loss of activity are discussed by modeling and comparison of the newly synthesized aaSoA derivatives with their parent aaSA analogues.
authors: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Bharat
authors: B
authors: Gadakh
authors: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Simon
authors: S
authors: Smaers
authors: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Jef
authors: J
authors: Rozenski
authors: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors: Mathy
authors: M
authors: Froeyen
authors: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium. Electronic address: arthur.vanaerschot@rega.kuleuven.be.
authors: Arthur
authors: A
authors: Van Aerschot
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology; D002176:Candida albicans / Q000187:drug effects; D020134:Catalytic Domain; D003839:Deoxyadenosines / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000890:Anti-Infective Agents; D003839:Deoxyadenosines; D004791:Enzyme Inhibitors; D013449:Sulfonamides; C033714:5'-deoxyadenosine; D000604:Amino Acyl-tRNA Synthetases; D000241:Adenosine
keywords: Amino acids; Antibacterial; Inhibitors; Nucleosides; Sulfonamides; tRNA synthetase