S-2,omega-Diaminoalkyl dihydrogen phosphorothioates as antiradiation agents.
To enable further structure-activity comparisons among radioprotective phosphorothioates, S-2,omega-diaminoalkyl dihydrogen phosphorothioates were synthesized from L-2,4-diaminobutyric acid, L-ornithine, L-lysine, and DL-2,7-diaminoheptanoic acid as homologues of S-2,3-diaminopropyl dihydrogen phosphorothioate (4) and as isomeric analogues of S-2-[(omega-aminoalkyl)amino]ethyl dihydrogen phosphorothioates (e.g., 1). The preferred route that evolved from exploratory trials retained optical activity and involved the reduction of methyl 2,omega-bis(benzoylamino)alkanoates with lithium borohydride, debenzoylation-bromodehydroxylation, and reaction of the resulting 1-(bromomethyl)-1,omega-alkanediamine dihydrobromides with trisodium phosphorothioate. The products of an alternative route that involved the reduction of phthaloylated intermediates with sodium borohydride were racemic. Exploratory conversions of N-(omega-alkenyl)phthalimides failed to provide suitable precursors of the target compounds. In terms of a protective index, these homologues were significantly more radioprotective than the parent phosphorothioate 4 when administered intraperitoneally to mice prior to whole-body gamma irradiation. The homologues derived from L-lysine also showed good peroral activity. No apparent difference was observed in the protection afforded by optically active homologues and the corresponding racemates.
D000818:Animals; D002588:Cesium Radioisotopes; D004305:Dose-Response Relationship, Drug; D005720:Gamma Rays; D008722:Methods; D051379:Mice; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D011837:Radiation-Protective Agents / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002588:Cesium Radioisotopes; D009946:Organothiophosphorus Compounds; D011837:Radiation-Protective Agents