Synthesis and modulation of cytokine production by two new adamantane substituted acyclic desmuramyldipeptide analogs

Two new adamantyl-desmuramyldipeptides LK 415 and LK 517 with 1-adamantylca rboxamido moiety as a replacement for muramyldipeptide's N-acetylglucosamin e fragment were synthesized. Their efficacy to modulate the production of c ytokines was measured in vitro in ionomycin and phorbol-12-myristate-13-ace tate (PMA) activated cultures of human peripheral blood mononuclear cells ( PBMC), co-incubated with the substances tested. The results were compared w ith the activity of muramyldipeptide (MDP). All three substances are strong up-regulators of IL-12 synthesis and hence of the IFN gamma synthesis as w ell. While MDP and LK 415 are relatively ineffective in modulation of IL-2, IL-4 and IL-10 production in vitro, the synthesis of all three cytokines i s cosiderably up-regulated when peripheral blood mononuclear cells are co-i ncubated with LK 517. It seems likely that the introduction of the diethyl phosphonate moiety into LK 517 is of great importance for the augmented T-c ell cytokine production.