作为PPE和HLE抑制剂的N1/C4-取代β-内酰胺的合成与评价

Synthesis and evaluation of N1/C4-substituted beta-lactams as PPE and HLE inhibitors.

作者信息

Gérard Stéphane, Galleni Moreno, Dive Georges, Marchand-Brynaert Jacqueline

机构信息

Unité de Chimie Organique et Médicinale, Université catholique de Louvain, Bâtiment Lavoisier, place Louis Pasteur 1, B-1348, Louvain-la-Neuve, Belgium.

出版信息

Bioorg Med Chem. 2004 Jan 2;12(1):129-38. doi: 10.1016/j.bmc.2003.10.009.

DOI:10.1016/j.bmc.2003.10.009

PMID:14697778

Abstract

4-(Alkylamino)carbonyl-1-(alkoxy)carbonyl-2-azetidinones (9-11) have been prepared in five steps from 4-(benzyloxy)carbonyl-1-(t-butyldimethyl)silyl-2-azetidinone (1). The beta-lactam reactivity of 9 has been established by 1H NMR experiment. Compound 11 was a good reversible inhibitor of PPE and HLE. Based on theoretical design, series of 2-azetidinones (12-17) and 4-(alkoxy)carbonyl-2-azetidinones (18-21) bearing various carbonyl (ester, thiolester, amide) and thiocarbonyl (thioamide) functionalities at position N1 were similarly prepared. In the absence of C4-substituent, the compounds were inactive against elastases. On the other hand, 4-(benzyloxy)carbonyl-1-(ethylthioxy)carbonyl-2-azetidinone (19) and 4-(benzyloxy)carbonyl-1-(benzylamino)thiocarbonyl-2-azetidinone (21) were both good reversible inhibitors, but acting most probably via different mechanisms (enzymic processing of the exocyclic ester function or beta-lactam ring opening).

摘要

4-（烷基氨基）羰基-1-（烷氧基）羰基-2-氮杂环丁酮（9-11）由4-（苄氧基）羰基-1-（叔丁基二甲基）甲硅烷基-2-氮杂环丁酮（1）经五步反应制备而成。通过¹H NMR实验确定了9的β-内酰胺反应活性。化合物11是PPE和HLE的良好可逆抑制剂。基于理论设计，类似地制备了一系列在N1位带有各种羰基（酯、硫酯、酰胺）和硫羰基（硫代酰胺）官能团的2-氮杂环丁酮（12-17）和4-（烷氧基）羰基-2-氮杂环丁酮（18-21）。在没有C4取代基的情况下，这些化合物对弹性蛋白酶无活性。另一方面，4-（苄氧基）羰基-1-（乙硫氧基）羰基-2-氮杂环丁酮（19）和4-（苄氧基）羰基-1-（苄基氨基）硫羰基-2-氮杂环丁酮（21）都是良好的可逆抑制剂，但作用机制很可能不同（环外酯官能团的酶促加工或β-内酰胺环开环）。