title: Synthesis and activity of dipeptides, linked to targeting ligands, as specific NK cell enhancers.
abstract: Water soluble analogues of the lipophilic immunostimulant, octadecyl D-alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the ability to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter chain alcohol, 6-(D-alanyl-L-glutaminylamino)hexan-1-ol, 9, displayed an in vitro stimulation of NK cells comparable to that of interleukin 2 (IL 2). However, when the hydroxyl of 9 was linked to L-fucose to yield 1-beta-[6-(D-alanyl-L-glutaminylamino)hex-1-yl]-L- fucopyranose (BCH-2537, 1), the observed stimulation of NK cells was greater than that observed with IL 2. Further evaluation of these compounds revealed that the improved in vitro activity of BCH-2537 was more pronounced in vivo. That is, while both compounds significantly increased splenic NK cells, only BCH-2537 significantly increased the activity of these cells in vivo. In terms of a structure-activity relationship, NK cell activity was sensitive to minor structural modifications. It was influenced by conservative substitutions within the dipeptide, the length of the hydrocarbon chain, and the functionality at the end of the chain. No other compound enhanced NK cell activity to the extent exhibited by BCH-2537, although a few were equipotent to 9.
authors.affiliation: Department of Medicinal Chemistry, BioChem Thérapeutique Inc., 275 Boulevard Armand-Frappier, Laval, Québec, H7V 4A7, Canada.
authors.forename: S D
authors.initials: SD
authors.lastname: Abbott
authors.forename: L
authors.initials: L
authors.lastname: Gagnon
authors.forename: M
authors.initials: M
authors.lastname: Lagraoui
authors.forename: S
authors.initials: S
authors.lastname: Kadhim
authors.forename: G
authors.initials: G
authors.lastname: Attardo
authors.forename: B
authors.initials: B
authors.lastname: Zacharie
authors.forename: C L
authors.initials: CL
authors.lastname: Penney
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005643:Fucose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000441:Hexanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D016897:Respiratory Burst / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
chemical_list: C112426:1-(6-(alanyl-glutaminylamino)hex-1-yl)fucopyranose; C112427:6-(alanyl-glutaminylamino)hexan-1-ol; D000276:Adjuvants, Immunologic; D004151:Dipeptides; D000441:Hexanols; D008934:Mitogens; D005643:Fucose