Synthesis and evaluation of a difluoromethylene analogue of sphingomyelin as an inhibitor of sphingomyelinase.
A sphingomyelin analogue 2, in which the long alkenyl chain and the phosphodiester moiety of sphingomyelin were replaced by a phenyl and an isosteric difluoromethylenephosphonic acid, was prepared to evaluate its inhibitory potency to sphingomyelinase. The analogue non-competitively inhibited the neutral sphingomyelinase in bovine brain microsomes with an IC50 of 400 microM. The compound had the ability to suppress tumor necrosis factor alpha-induced apoptosis of PC-12 neurons at a low concentration of 0.1 microM.
Yokomatsu
T
T
School of Pharmacy, Tokyo University of Pharmacy & Life Science, Hachioji, Japan. yokomatu@ps.toyaku.ac.jp
Takechi
H
H
Akiyama
T
T
Shibuya
S
S
Kominato
T
T
Soeda
S
S
Shimeno
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain; D002417:Cattle; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors*; D013109:Sphingomyelins / Q000138:chemical synthesis* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004791:Enzyme Inhibitors; D063065:Organophosphonates; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; D013108:Sphingomyelin Phosphodiesterase