Howard Nigel I, Bugg Timothy D H
Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
Bioorg Med Chem. 2003 Jul 17;11(14):3083-99. doi: 10.1016/s0968-0896(03)00270-0.
A series of 5'-uridinyl dipeptides were synthesised which mimic the amino terminal chain of nucleoside antibiotic mureido omycin A. Aminoacyl-beta-alanyl- and aminoacyl-N-methyl-beta-alanyl- dipeptides were attached either via an ester linkage to the 5'-hydroxyl of uridine, or via an amide linkage to 5'-amino-5'-deoxyuridine. The most active inhibitor of Escherichia coli phospho-MurNAc-pentapeptide translocase (MraY) was 5'-O-(L-Ala-N-methyl-beta-alanyl)-uridine (13l), which also showed 97% enzyme inhibition at 2.35 mM concentration, and showed antibacterial activity at 100 microg/mL concentration against Pseudomonas putida. Both the central N-methyl amide linkage and a 5' uridine ester linkage were required for highest biological activity. Enzyme inhibition was shown to be competitive with Mg(2+). It is proposed that the primary amino terminus of the inhibitor binds in place of the Mg(2+) cofactor at the MraY active site, positioned via a cis-N-methyl amide linkage.
合成了一系列5'-尿苷二肽，它们模拟核苷抗生素多聚霉素A的氨基末端链。氨酰基-β-丙氨酰基-和氨酰基-N-甲基-β-丙氨酰基-二肽通过酯键连接到尿苷的5'-羟基上，或者通过酰胺键连接到5'-氨基-5'-脱氧尿苷上。大肠杆菌磷酸化MurNAc-五肽转位酶（MraY）最有效的抑制剂是5'-O-（L-丙氨酰基-N-甲基-β-丙氨酰基）-尿苷（13l），其在2.35 mM浓度下也表现出97%的酶抑制率，并且在100 μg/mL浓度下对恶臭假单胞菌具有抗菌活性。最高生物活性需要中央N-甲基酰胺键和5'尿苷酯键。酶抑制作用显示与Mg(2+)具有竞争性。据推测，抑制剂的伯氨基末端在MraY活性位点取代Mg(2+)辅因子结合，通过顺式-N-甲基酰胺键定位。
