Two-step
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The newly developed and very promising acetylcholinesterase reactivator (E)-1-(2-hydroxyiminomethylpyridinium)-4-(4-hydroxyiminomethylpyridinium)-but-2-ene dibromide was prepared using two different pathways via a two-step synthesis involving the appropriate (E)-1-(4-bromobut-2-enyl)-2- or 4-hydroxyiminomethyl-pyridinium bromides. Afterwards, purities and yields of the desired product prepared by both routes were compared. Finally, its potency to reactivate several nerve agent-inhibited acetylcholinesterases was tested.
Linear tri- and tetrapeptide precursors of 2,5-piperazinedione were prepared and their conversion to spirocyclic dipeptidase enzymes, the spirocyclic dipeptides (SpDp) were generated from the precursors by a two-step mechanism consisting in the proteolytic release of the C-terminal dipeptide ethyl ester and its subsequent spontaneous cyclization. After intraperitoneal administration of urokinase and Ac-Leu-Lys-Gly-Acp-OEt, a SpDp precursor targeted to endogenous plasmin, or the administration of the activated Hageman factor fragment and Ac-Leu-Arg-Ala-Acp-OEt, a SpDp precursor, targeted to endogenous kallikrein, the generated corresponding C-terminal dipeptide ethylester intermediates and SpDp, cyclo(Gly-Acp) and cyclo (Ala-Acp), respectively, were detected in the blood serum of C57B1 mice. Suppression of partial amnesia induced by sodium nitrite was observed in rats where it was subcutaneously administered with H-Leu-Ala-Acp-OEt, a peptide precursor of alaptide, the active SpDp, i.e. cyclo(1-amino-1-cyclopentanecarbonyl-L-alanyl).
