RESUMO
A method for the stereocontrolled synthesis of a bacterial phosphoglycolipid (PGL1) isolated from thermophilic bacteria is described. The key features of the synthesis include a highly α-selective glycosylation reaction between a trichloroacetimidate donor and a D-lyxose-derived primary alcohol acceptor and the late-stage incorporation of the phospholipid.
Assuntos
Acetamidas/química , Adjuvantes Imunológicos/síntese química , Cloroacetatos/química , Pentoses/química , Fosfolipídeos/síntese química , Thermus/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Glicosilação , Estrutura Molecular , Fosfolipídeos/química , Fosfolipídeos/farmacologia , Silanos/químicaAssuntos
Aldeídos/química , Técnicas de Química Sintética/métodos , Álcoois/síntese química , Aldeídos/síntese química , Benzodiazepinas/síntese química , Produtos Biológicos/síntese química , Furanos/síntese química , Lactamas/síntese química , Nucleosídeos/síntese química , Piridinas/síntese química , Quinolinas/síntese químicaRESUMO
A new series of monosaccharide-based glycolipids devoid of phosphate groups and with two lipid chains were rationally designed by varying the lipid chain lengths and saccharide structure of a α-GalCer-derived lead compound (CCL-34) that is a potent TLR4 agonist. The NF-κB activity of a 60-membered galactosyl serine-based synthetic library containing compounds with various lipid chain lengths was measured in a HEK293 cell line that stably expressed human TLR4, MD2, and CD14 (293-hTLR4/MD2-CD14). The results showed that the optimal carbon chain lengths for the lipid amine and fatty acid to activate TLR4 were 10-11 and 12, respectively. Evaluation of a 20-membered synthetic glycosyl serine-based lipid library containing compounds with various saccharide moieties and fixed lipid chain lengths revealed that the galactose moiety in CCL-34 could be replaced by glucose without loss of activity (CCL-34-S3 and CCL-34-S16). Changing the orientation of the anomeric glycosidic bond of CCL-34 resulted in a complete loss of activity (ß-CCL34). Surprisingly, a change in configuration of the anomeric glycosidic bond in a glucosyl glycolipid is tolerable (CCL-34-S14). Another noteworthy observation is that the activity of a l-fucosyl derived glycolipid (CCL-34-S13) was comparable to that of CCL-34. In sum, this study determines the structural features that are crucial for an optimal TLR4-stimulating activity. It also provides several molecules with immunostimulating potential.
Assuntos
Glicolipídeos/síntese química , Receptor 4 Toll-Like/agonistas , Linhagem Celular , Glicolipídeos/farmacologia , Humanos , Estrutura Molecular , NF-kappa B/metabolismo , Serina/química , Relação Estrutura-AtividadeRESUMO
A new and highly efficient methodology for the construction of synthetically important highly O-functionalized enantiopure 2,3,4-trisubstituted tetrahydrofurans with three contiguous stereocenters is reported.
