Synthesis and pharmacological activities of novel cyclic disulfide and cyclic sulfide derivatives as hepatoprotective agents.
In order to search for anti-hepatitis drugs, we synthesized a series of eight- and nine-membered cyclic disulfides (1) and six- and seven-membered cyclic sulfides (2) and evaluated them for ability to reduce mortality in the model of acute hepatic failure induced by Propionibacterium acnes-lipopolysaccharide in mice. Compounds 1 were synthesized by oxidative cyclization of the corresponding dithiol derivatives (3) with diethyl bromomalonate or iodine. Compounds 2 were prepared from the methyl esters of 1 by desulfurization with tris(diethylamino)phosphine followed by deprotection. Compounds 1 were generally found to be more active than compounds 2. Compound 1b (SA3443) was found to exhibit potent protective activity. The synthesis and structure-activity relationships are discussed.
Ito
S
S
Central Research Laboratories, Santen Pharmaceutical Co., Ltd., Osaka, Japan.
Ota
A
A
Suhara
H
H
Tabashi
K
K
Kawashima
Y
Y
D000818:Animals; D001392:Azocines / Q000138:chemical synthesis / Q000627:therapeutic use; D004195:Disease Models, Animal; D004220:Disulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D006501:Hepatic Encephalopathy / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011425:Propionibacterium acnes; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
D001392:Azocines; D004220:Disulfides; D008070:Lipopolysaccharides; D013440:Sulfides; C069788:SA 3443