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.
Highlights
Bacterial cell wall components like proteoglycans, lipopolysaccharides and lipoproteins possess strong immunostimulating activities
The dipeptide part of the lead compound was modified by introducing a phosphonamide isostere instead of the amide bond between Lalanine and D-glutamic acid, yielding new muramyl dipeptide (MDP) analogues 5 and 9
Replacement of the N-acetylmuramyl moiety with various acyl groups represents an important approach in the design and synthesis of new immunologically active MDP analogues, as demonstrated by FK-156 [7], pimelautide [8], 7-(oxoacyl)-L-alanyl-D-isoglutamines [9], some carbocyclic MDP analogues [10,11], and by the adamantyl-substituted MDP analogue LK 415 [12]
Summary
Bacterial cell wall components like proteoglycans, lipopolysaccharides and lipoproteins possess strong immunostimulating activities. The dipeptide part of the lead compound was modified by introducing a phosphonamide isostere instead of the amide bond between Lalanine and D-glutamic acid (or D-isoglutamine), yielding new MDP analogues 5 and 9. Stimulated by the results of preliminary immunological tests of selected phosphorus MDP analogues [17], we present the syntheses of three new phosphapeptides related to LK 423, whose amide bonds between L-alanyl and D-glutamate moieties are replaced by phosphonamidate and phosphonate bonds, respectively.
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