CARBOCYCLIC NUCLEOSIDES AS INHIBITORS OF HUMAN TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION - EFFECTS OF THE STEREOISOMERS OF (3-HYDROXYCYCLOPENTYL)ADENINES

A series of four structurally related carbocyclic nucleosides (6a, 6b, 10a, and 10b) were synthesized and evaluated for their ability to inh ibit tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) production from human primary macroph ages. These compounds had little effect on the production of IL-1 beta and IL-6. It was determined that compound 10a was the most potent inh ibitor of TNF-alpha production (IC50 = 10 mu M), having 2-5-fold more activity compared to its enantiomer 10b or its diastereomers 6a and 6b . In addition, these compounds were also tested for their ability to p rotect mice against lethal challenges of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Compound 10a showed superior protective effec ts (100% protection) compared to its enantiomer 10b or its diastereome rs 6a and 6b when it was administered to mice which were challenged wi th 3 times the LD(100) dose of LPS.