Abbott S D, Gagnon L, Lagraoui M, Kadhim S, Attardo G, Zacharie B, Penney C L
Department of Medicinal Chemistry, BioChem Thérapeutique Inc., 275 Boulevard Armand-Frappier, Laval, Québec, H7V 4A7, Canada.
J Med Chem. 1998 May 21;41(11):1909-26. doi: 10.1021/jm970734v.
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.
合成了亲脂性免疫刺激剂十八烷基-D-丙氨酰-L-谷氨酰胺（BCH-527）的水溶性类似物，并对其刺激自然杀伤（NK）细胞的能力进行了评估。其中一种化合物，即BCH-527的十八烷基链被较短链醇6-(D-丙氨酰-L-谷氨酰胺基氨基)己醇（9）取代，在体外对NK细胞的刺激作用与白细胞介素2（IL-2）相当。然而，当9的羟基与L-岩藻糖连接生成1-β-[6-(D-丙氨酰-L-谷氨酰胺基氨基)己-1-基]-L-岩藻吡喃糖（BCH-2537，1）时，观察到对NK细胞的刺激作用大于IL-2。对这些化合物的进一步评估表明，BCH-2537体外活性的提高在体内更为显著。也就是说，虽然两种化合物都显著增加了脾脏NK细胞，但只有BCH-2537在体内显著提高了这些细胞的活性。就构效关系而言，NK细胞活性对微小的结构修饰敏感。它受二肽内保守取代、烃链长度和链末端官能团的影响。没有其他化合物能像BCH-2537那样增强NK细胞活性，不过有几种与9等效。
