Zacharie B, Gagnon L, Attardo G, Connolly T P, St-Denis Y, Penney C L
Department of Medicinal Chemistry, BioChem Therapeutic Inc., Laval, Quebec.
J Med Chem. 1997 Aug 29;40(18):2883-94. doi: 10.1021/jm960844m.
A series of 6-substituted purinyl alkoxycarbonyl amino acids were synthesized and evaluated for their ability to stimulate cytotoxic T lymphocytes (CTLs) and the mixed lymphocyte reaction (MLR). A few of these compounds, in particular [[5-[6-(N,N-dimethylamino)purin-9-yl]pentoxy]-carbonyl]D-arginine (BCH-1393, 4a), displayed an in vitro stimulation of CTLs comparable to interleukin 2 (IL 2). BCH-1393 increased the CTL response between 10(-9) M and 10(-5) M. Further, this potent in vitro activity was reflected as a significant increase in CTL cell number in vivo. However, immunophenotyping of some of the other equipotent compounds did not reveal a parallel relative increase in CTLs in vivo. It was difficult to formulate a rigorous structure-activity relationship based on in vitro CTL activity. Nevertheless, the activity was dependent upon the nature of the 6-substituent on the purine, the type and stereochemistry of the amino acid, and the distance and spatial freedom between the purine and amino acid as defined by the length and rigidity of the linker. These compounds were generally nontoxic, as exemplified by BCH-1393. BCH-1393 is a promising immunostimulant which may be targeted for those disease states which require an increased CTL or TH1 type response.
合成了一系列6-取代的嘌呤基烷氧羰基氨基酸，并评估了它们刺激细胞毒性T淋巴细胞（CTL）和混合淋巴细胞反应（MLR）的能力。其中一些化合物，特别是[[5-[6-(N,N-二甲基氨基)嘌呤-9-基]戊氧基]羰基]D-精氨酸（BCH-1393，4a），在体外对CTL的刺激作用与白细胞介素2（IL-2）相当。BCH-1393在10^(-9) M至10^(-5) M之间增强了CTL反应。此外，这种强大的体外活性在体内表现为CTL细胞数量的显著增加。然而，对其他一些等效化合物的免疫表型分析并未揭示体内CTL有相应的相对增加。基于体外CTL活性难以建立严格的构效关系。尽管如此，活性取决于嘌呤上6-取代基的性质、氨基酸的类型和立体化学，以及由连接子的长度和刚性所定义的嘌呤与氨基酸之间的距离和空间自由度。这些化合物一般无毒，BCH-1393就是例证。BCH-1393是一种有前景的免疫刺激剂，可针对那些需要增强CTL或TH1型反应的疾病状态。
