Gadakh Bharat, Smaers Simon, Rozenski Jef, Froeyen Mathy, Van Aerschot Arthur
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Eur J Med Chem. 2015 Mar 26;93:227-36. doi: 10.1016/j.ejmech.2015.02.010. Epub 2015 Feb 9.
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.
由于氨酰化反应产率低以及随后的缀合反应会伴随形成环状腺苷衍生物，氨基酰 - 氨磺酰腺苷（aaSAs）及其肽基缀合物作为氨酰 - tRNA合成酶（aaRS）抑制剂的合成仍然存在问题。为了减少这种不良副反应，我们旨在制备相应的氨基酰磺酰胺（aaSoA）类似物，作为aaSAs衍生物更稳定的替代物。在aaSAs类似物中删除5'-氧应该使C-5'的亲电性降低，从而提高氨基酰氨基磺酸酯类似物的稳定性。因此，我们合成了六种磺酰胺，并比较了它们对各自aaSAs类似物的活性。然而，除了天冬氨酰衍生物外，新化合物不能抑制相应的aaRS。通过对新合成的aaSoA衍生物与其母体aaSAs类似物进行建模和比较，讨论了这种活性丧失的可能原因。
