Carbocyclic Nucleosides as Inhibitors of Human Tumor Necrosis Factor-α Production:  Effects of the Stereoisomers of (3-Hydroxycyclopentyl)adenines

• Published in: Journal of medicinal chemistry Vol. 39; no. 13; pp. 2615 - 2620
• Main Authors: Borcherding, David R, Peet, Norton P, Munson, H. Randall, Zhang, Hao, Hoffman, Paul F, Bowlin, Terry L, Edwards, Carl K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 21.06.1996; Amer Chemical Soc
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacology; Adenosine - analogs & derivatives; Adenosine - chemistry; Adenosine - pharmacology; Animals; Biological and medical sciences; Chemistry, Medicinal; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; Galactosamine - pharmacology; Humans; Immunomodulators; Interleukin-1 - biosynthesis; Interleukin-6 - biosynthesis; Life Sciences & Biomedicine; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Stereoisomerism; Tumor Necrosis Factor-alpha - biosynthesis; ADENOSINE; MICE; RECEPTORS; ENDOTOXIN; Shock; Purine nucleoside; Interleukin 6; Lipopolysaccharide; Inhibition; Secondary alcohol; Chemical synthesis; Monocyclic compound; Endotoxemia; Tumor necrosis factor α; Galactosamine; Human; Rodentia; Antiinflammatory agent; Cytokine; Interleukin 1β; In vitro; Biological activity; Immunomodulator; Infection; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Diastereomer
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950906t

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-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) production from human primary macrophages. These compounds had little effect on the production of IL-1β and IL-6. It was determined that compound 10a was the most potent inhibitor of TNF-α production (IC50 = 10 μM), 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.