SYNTHESIS AND ACTIVITY OF DIPEPTIDES, LINKED TO TARGETING LIGANDS, ASSPECIFIC NK CELL ENHANCERS

Water soluble analogues of the lipophilic immunostimulant, octadecyl D -alanyl-L-glutamine, BCH-527, were synthesized and evaluated for the a bility to stimulate natural killer (NK) cells. One of these compounds in which the octadecyl chain of BCH-527 was replaced with a shorter ch ain 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 yiel 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, w hile 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 sensi tive to minor structural modifications. It was influenced by conservat ive substitutions within the dipeptide, the length of the hydrocarbon chain, and the functionality at the end of the chain. No other compoun d enhanced NK cell activity to the extent exhibited by BCH-2537, altho ugh a few were equipotent to 9.