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 inhibit tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) production from human primary macrophages. 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 inhibitor of TNF-alpha production (IC50 = 10 microM), 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 protect mice against lethal challenges of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). Compound 10a showed superior protective effects (100% protection) compared to its enantiomer 10b or its diastereomers 6a and 6b when it was administered to mice which were challenged with 3 times the LD100 dose of LPS.
Borcherding
D R
DR
Hoechst Marion Roussel, Inc., Cincinnati, Ohio 45215-6300, USA.
Peet
N P
NP
Munson
H R
HR
Zhang
H
H
Hoffman
P F
PF
Bowlin
T L
TL
Edwards
C K
CK
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005688:Galactosamine / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C100458:1-(9-adenyl)cyclopentan-3-ol; D003517:Cyclopentanes; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D000225:Adenine; D000241:Adenosine