Organic disulfides and related substances. 38. Some disulfide and trisulfide sulfinate salts as antiradiation drugs.
The trisulfide disulfinate [Na32S(CH2)4S]2S (2) is an antiradiation drug which is atypical in having no nitrogen function. At low dose levels of 37.5 and 18.5 mg/kg intraperitoneally (ip), 2 protected respectively about 82 and 35% of lethally irradiated mice. By the oral route (po), 150 mg/kg of 2 protected about 73%, and 75 mg/kg protected about 20%. The LD50 either ip or po exceeded 900 mg/kg. Although a 2,3-diacetoxy analog 3 was inactive, cyclic disulfide and trisulfide sulfinate analogs showed promice. Among these, a sulfinate moiety is related to a di- or trisulfie moiety in the sense of 1,8 in a naphthyl system (4,5), 2,2' in a biphenyl system (6-9), and alpha,alpha' in an o-xylyl system (10,11). The 1,8-naphthyl disulfide sulfinate 4 was not tested biologically because a marked neighboring group effect of -SO2Na on -SS- caused rapid cyclization to the parent disulfide dioxide 14; the corresponding trisulfide 5 was more stable but only slightly protective. Other analogs lacking the coplanarity of 4 also were more stable. The biphenyl compounds 6 and 7 were quite active ip (e.g., 7 led to 90% survival at 4.6 mg/kg, with LD50 EQUALS 130 mg/kg, although protection with 6 and 7 at the doses given po was only fair). Dichloro counterparts 8 and 9 offered no advantages over 6 and 7. The xylylene compounds 10 and 11 were roughly comparable to each other by ip and op routes (e.g., given ip, 10 led to 93-100% survival at 75 mg/kg, with LD50 GREATER THAN 950 mg/kg; given po, 10 gave 100% survival at 60 mg/kg, with LD50 GREATER THAN 900 mg/kg). Compounds 7 and 11 join 2 as promising antiradiation drugs that lack the usual nitrogen function. The fact that sulfinate salts show activity, both ip and po, suggests that the -SO2Na moiety deserves more attention in medicinal chemistry. Hydration of sulfinate salts often made analytical characterization difficult. Confirmatory evidence for typical structures is given.
D000284:Administration, Oral; D000818:Animals; D002588:Cesium Radioisotopes; D004220:Disulfides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D005720:Gamma Rays; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D051379:Mice; D008815:Mice, Inbred Strains; D011830:Radiation Effects; D011837:Radiation-Protective Agents / Q000138:chemical synthesis* / Q000633:toxicity; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D013441:Sulfinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity
D002588:Cesium Radioisotopes; D004220:Disulfides; D011837:Radiation-Protective Agents; D013440:Sulfides; D013441:Sulfinic Acids