Decicco C P, Nelson D J, Luo Y, Shen L, Horiuchi K Y, Amsler K M, Foster L A, Spitz S M, Merrill J J, Sizemore C F, Rogers K C, Copeland R A, Harpel M R
Department of Medicinal Chemistry, DuPont Pharmaceuticals Company, Experimental Station, PO Box 80400, Wilmington, DE 19880, USA.
Bioorg Med Chem Lett. 2001 Sep 17;11(18):2561-4. doi: 10.1016/s0960-894x(01)00499-1.
Analogues of glutamyl-gamma-boronate (1) were synthesized as mechanism-based inhibitors of bacterial Glu-tRNA(Gln) amidotransferase (Glu-AdT) and were designed to engage a putative catalytic serine nucleophile required for the glutaminase activity of the enzyme. Although 1 provides potent enzyme inhibition, structure-activity studies revealed a narrow range of tolerated chemical changes that maintained activity. Nonetheless, growth inhibition of organisms that require Glu-AdT by the most potent enzyme inhibitors appears to validate mechanism-based inhibitor design of Glu-AdT as an approach to antimicrobial development.
合成了谷氨酰 -γ-硼酸酯（1）的类似物，作为基于机制的细菌谷氨酰胺 -tRNA（Gln）氨基转移酶（Glu - AdT）抑制剂，其设计目的是与该酶谷氨酰胺酶活性所需的假定催化丝氨酸亲核试剂结合。尽管化合物1具有强效的酶抑制作用，但构效关系研究表明，能保持活性的化学变化耐受范围很窄。尽管如此，最有效的酶抑制剂对需要Glu - AdT的生物体的生长抑制作用，似乎证实了基于机制设计Glu - AdT抑制剂作为抗菌药物开发方法的可行性。
