Synthesis and activity of 6-substituted purine linker amino acid immunostimulants.
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.
Zacharie
B
B
Department of Medicinal Chemistry, BioChem Therapeutic Inc., Laval, Quebec.
Gagnon
L
L
Attardo
G
G
Connolly
T P
TP
St-Denis
Y
Y
Penney
C L
CL
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000596:Amino Acids; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D016130:Immunophenotyping; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
D000276:Adjuvants, Immunologic; D000596:Amino Acids; C108181:BCH 1393; D007376:Interleukin-2; D011687:Purines; D001120:Arginine