synthesis of new lipophilic phosphonate and phosphonamidate analogues of n-acetylmuramyl-l-alanyl-d-isoglutamine related to lk 423的新合成亲脂性的膦酸酯和n-acetylmuramyl-l-alanyl-d-isoglutamine phosphonamidate类似物与路423.pdf

Molecules 2002, 7, 394-404 molecules ISSN 1420-3049 Synthesis of New Lipophilic Phosphonate and Phosphonamidate Analogues of N-Acetylmuramyl-L-alanyl-D-isoglutamine Related to LK 423 1 1,2 Stanislav Gobec*, and Uroš Urleb 1 University of Ljubljana, Faculty of Pharmacy, Aökerčeva 7, 1000 Ljubljana, Slovenia. 2 Lek d.d., Verovökova 57, 1000 Ljubljana, Slovenia. * Author to whom correspondence should be addressed; E-mail: gobecs@ffa.uni-lj.si Received: 9 January 2002; in revised form: 2 May 2002 / Accepted: 2 May 2002/ Published: 2 May 2002 Abstract: A syntheses of three new muramyl dipeptide (MDP) analogues related to LK 423 as potential immunomodulators are presented. The dipeptide part of the lead compound was modified by introducing a phosphonamide isostere instead of the amide bond between L- alanine and D-glutamic acid (or D-isoglutamine), yielding new MDP analogues 5 and 9. Furthermore, the amide bond between L-Ala and D-Glu was replaced by a phosphonate isostere, giving peptidyl phosphonate 14. The scope and limitations of the synthetic strategies employed are discussed. Keywords: Muramyl dipeptide, analogues, phosphonamidates, phosphonates, immunomodulators. Introduction Bacterial cell wall components like proteoglycans, lipopolysaccharides and lipoproteins possess strong immunostimulating activities. Since 1974 N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide, MDP, Figure 1) has been known as the smallest immunol