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N-Arylated-Lactam-Type Iminosugars as New Immunosuppressive Agents: Discovery, Optimization, and Biological Evaluation.
- Source :
- Chemistry - An Asian Journal; Aug2014, Vol. 9 Issue 8, p2260-2271, 12p
- Publication Year :
- 2014
-
Abstract
- We have previously described the discovery of N-alkylated iminosugars that showed immunosuppressive activity both in vitro and in vivo. Herein, we report the synthesis and biological evaluation of N-arylated lactam-type iminosugar derivatives. The synthesis started from simple monosaccharides and featured a Buchwald-Hartwig coupling reaction to construct the key N-aryl connection, thereby providing a highly diverse compound library. Structure-activity relationship studies, guided by a mouse-spleen-proliferation assay, led to the identification of ′hit′ compound 12 f. Subsequently, the systematic modification of compound 12 f afforded compounds 21 h, 21 k, 21 n, 21 t, and 21 x with improved activities (IC<subscript>50</subscript>=12-30 μ M) and low Jurkat cytotoxicities (IC<subscript>50</subscript>>100 μ M). These new compounds also inhibited the secretion of IFN-γ and IL-4, which are hallmark cytokines of Th1 and Th2 cells, respectively. This work demonstrated that the N-arylated iminosugar structure represents a new scaffold with immunosuppressive activity. [ABSTRACT FROM AUTHOR]
- Subjects :
- IMINOSUGARS
CYTOKINES
CHEMICAL synthesis
IMMUNOSUPPRESSIVE agents
IMINO compounds
Subjects
Details
- Language :
- English
- ISSN :
- 18614728
- Volume :
- 9
- Issue :
- 8
- Database :
- Complementary Index
- Journal :
- Chemistry - An Asian Journal
- Publication Type :
- Academic Journal
- Accession number :
- 97252568
- Full Text :
- https://doi.org/10.1002/asia.201400023