Synthesis and Activity of 6-Substituted Purine Linker Amino Acid Immunostimulants
- 1 August 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (18), 2883-2894
- https://doi.org/10.1021/jm960844m
Abstract
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.Keywords
This publication has 11 references indexed in Scilit:
- A short synthesis of 4-substituted 1-(hydroxyalkyl)-1H-pyrazolo[3,4-d]pyrimidinesTetrahedron, 1996
- Therapeutic potentiation of the immune system by costimulatory Schiff-base-forming drugsNature, 1995
- Induction of apoptosis in mature T cells by tumour necrosis factorNature, 1995
- Role of CD26/dipeptidyl peptidase IV in human immunodeficiency virus type 1 infection and apoptosis.Proceedings of the National Academy of Sciences of the United States of America, 1994
- Potentiation of immune responses in mice by a new inosine derivative—Methyl inosine monophosphate (MIMP)International Journal of Immunopharmacology, 1992
- A new peptide analog (RM06) modulates the growth of hematopoietic cellsInternational Journal of Immunopharmacology, 1991
- A new synthetic route to prostaglandinsTetrahedron Letters, 1986
- Problems and Challenges in the Use of Immunomodulating AgentsInternational Archives of Allergy and Immunology, 1985
- Selective cleavage of ethers by sodium iodide-acyl chlorideTetrahedron Letters, 1982
- 4-Hydroxy-3-nitro-2-quinolones and related compounds as inhibitors of allergic reactionsJournal of Medicinal Chemistry, 1975