SYNTHESIS AND ACTIVITY OF 6-SUBSTITUTED PURINE LINKER AMINO-ACID IMMUNOSTIMULANTS

A series of 6-substituted purinyl alkoxycarbonyl amino acids were synt hesized and evaluated for their ability to stimulate cytotoxic T lymph ocytes (CTLs) and the mixed lymphocyte reaction (MLR). A few of these compounds, in particular ethylamino)purin-9-yl]pentoxy]-carbonyl]D-arg inine (BCH-1393, 4a), displayed an in vitro stimulation of CTLs compar able to interleukin 2 (IL 2). BCH-1393 increased the CTL response betw een 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. Howeve r, 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 v itro CTL activity. Nevertheless, the activity was dependent upon the n ature of the B-substituent on the purine, the type and stereochemistry of the amino acid, and the distance and spatial freedom between the p urine and amino acid as defined by the length and rigidity of the link er. These compounds were generally nontoxic, as exemplified by BCH-139 3. BCH-1393 is a promising immunostimulant which may be targeted for t hose disease states which require an increased CTL or TH1 type respons e.