title: Protein synthesis by mammalian cells treated with C-3-modified analogs of the 12,13-epoxytrichothecenes T-2 and T-2 tetraol.
abstract: Modification at the C-3 position of the trichothecenes T-2 and T-2 tetraol affected their ability to inhibit protein synthesis in African green monkey kidney (Vero) and mouse erythroleukemia cells. Replacement of the 3-hydroxyl of T-2 with hydrogen caused a 24-fold decrease in activity, whereas acetylation resulted in a 500-to 1,000-fold decrease. Protection of the 3-hydroxyl with a tetrahydropyranyl moiety gave an analog that was 37-fold more inhibitory to Vero than to mouse erythroleukemia cells; with the other analogs a similar effect on protein synthesis was found for both types of cells. The analogs obtained after alkaline hydrolysis were much less potent than the parent trichothecenes. The 3-tetrahydropyranyl-modified analog was equivalent in potency to T-2 tetraol, while the deoxygenated species was at least threefold less potent. All T-2 analogs caused some degree of polysome "runoff," thereby demonstrating that these species inhibit protein synthesis at the chain initiation stage when added at their 50% infective dose concentrations or lower. From these results, we suggest that the 3-hydroxyl moiety is essential for T-2 to exhibit such high activity on eucaryotic cell protein synthesis and that modification at the C-3 position decreases but does not eliminate this activity.
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D007668:Kidney; D004915:Leukemia, Erythroblastic, Acute; D007942:Leukemia, Experimental; D051379:Mice; D011132:Polyribosomes / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013605:T-2 Toxin / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D012717:Sesquiterpenes; C046700:T-2 tetraol; D013605:T-2 Toxin