Synthesis and Pharmacological Activities of Novel Cyclic Disulfide and Cyclic Sulfide Derivatives as Hepatoprotective Agents.

Abstract

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.

Suppression of laser‐induced choroidal neovascularization by oral administration of SA3443 in mice

“…SA3443 was shown to modulate immune reactions [8][9][10][11][12][13][14][15][16][17][18][19]. This and other studies have shown that anti-inflammatory compounds including steroids [32], non-steroidal anti-inflammatory drugs (NSAIDs) [7,33] and other immunomodulatory drugs [5,34], suppress the CNV growth.…”

“…Each drug was administered just after the photocoagulation (on day 0) and given once daily thereafter. The concentrations were selected on the basis of previous studies [8][9][10][11][12][13][14][15][16][17][18][19].…”

“…The cyclic disulfide compound, SA3443 [(4R)-hexahydro-7,7-dimethyl-6-oxo-1, 2,5-dithiazocine-4-carboxylic acid], synthesized by oxidative cyclization of the dithiol derivatives, possesses various pharmacological activities [8][9][10][11][12][13][14][15][16][17][18][19]. In vivo, SA3443 protects liver damage in acute hepatic injuries induced chemically [9] or immunologically [11], and chronic liver inju-ries induced by carbon tetrachloride and heterologous serum [8].…”

Enantioselective radical cyclisation reactions of 4-substituted quinolones mediated by a chiral template

“…4-Chloroquinoline-Noxide (11) was synthesised in three steps starting from quinoline; 25 2,2-dimethyl-3-mercaptopropionic acid was synthesised from 3chloro-2,2-dimethylpropionic acid. 42 Starting Materials 2,2-Dimethyl-3-hydroxypropanethiol (12d). 2,2-Dimethyl-3mercaptopropionic acid (2.24 mmol, 300 g) dissolved in 8 mL anhydrous diethyl ether was added to 170 mg (4.47 mmol) lithiumaluminiumhydride in 12 mL anhydrous diethyl ether and the mixture was stirred at ambient temperature for 48 hours.…”

Synthesis and X-Ray Structure Determination of Diferrocenyl Disulfide

“…[1,2] Moreover, disulfides are useful synthetic intermediates in many chemical transformations. [3,4] Industrially, disulfides have been used extensively as vulcanizing reagents for rubber and elastomers, imparting excellent tensile strength.…”