Botulinum Toxin A Inhibitor Design, Synthesis And Evaluation

Botulinum toxin (BTX or BoNT) is a series of serotype toxin from A to G, which can be generated from clostridium botulinum under anaerobic conditions. BoNT/A is the most poisonous serotype among seven serotypes and possesses the characteristics of easily production, rare hypertoxicity and long duration of toxic paralysis, and it is considered to be one of the six most deadly biological poison. BoNT/A antibody has some limits in clinical treatment, it is only effective for anti-BoNT/A outside the presynaptic membrane cells. Therefore, design and synthesis of new small compounds for inhibition of BoNT/A is very important.In this work, based on the structural characteristics, binding mechanism, the three-dimensional structure of botulinum toxin A and a number of active compounds reported in references, we designed and synthesized two types of BoNT/A inhibitors, which belonged to the hydroxamic acids and toosendanin derivatives types, the latter was purified by HPLC. The structures of all synthesized compounds were determined with magnetic resonance hydrogen spectrum and mass spectrometry.The pharmacological activity of partial compounds and their acute toxicity was evaluated in vivo with Kunming mice and BoNT/A, the structure-activity relationship was briefly discussed on the preliminary results. The main work are summarized as follows:(1) 34 compounds were synthesized, and 20 of them are new compounds; (2) the acute toxicity of 17 was evaluated with mice, Except compound Cp20,Cp21andCp27, the rest of the evaluated compounds were innoxious to mice in the settled dosages; (3) The inhibitive activities of 8 hydroxamic acids were evaluated with mice and BoNT/A, and none compounds showed obvious pharmacological activity; (4)7 toosendanin derivatives were separated and purified, and inhibitive activities of 3 toosendanin derivatives were evaluated with mice and BoNT/A, one derivative Dmx-1 showed higher activity than toosendanin. This work will expand our knowledge for further design of the inhibitors of BoNT/A.