Preparation Of Terpene Alkaloids Based On Combinatorial Chemistry And Their Bioactivities

Combinatorial Chemistry is a technique which combined chemical synthesis, combinatorial theroy and computer aided design.It is also named combinatorial synthesis chemistry.Medicinal chemists can synthesize a lot of compounds using all kinds of chemical building blocks throw chemical synthesis in short times.Active compounds were screened from the combinatorial libraries.Today,people pay more attention to the building of natrual product derivatives libraries.More and more combinatorial libraries were constructed using natrual products as the template like terpenes,alkaloids.Iridoids and their glycosides constitute are an important class of natural products and they are biosynthetic precursors to a broad range of indole alkaloids,with joint biosynthetic key intermediates like secologanin.From the reaction of secologanin with tryptamine,we found it was the method of incorporation nitrogen atoms into iridoids or its glycosides to give iridoid alkaloids.Genipin,another iridoids glycoside was chosen as the starting materials to the biomimetic synthesis of monoterpene alkaloid compounds.Bioactivive substances was expected to find from the new synthesized compounds.Genipin was obtained from the enzymatic hydrolysis of geniposide,which was isolated from Gardenia jasminoides Eills..Genipin could be considered to be the analogue of glutaraldehyde,therefore it could easily react with amines,or nitrogen-containing compounds under various conditions to get monoterpene alkaloid-like compounds.The methods introduced to prepare the monoterpene alkaloid-like compounds were listed below:(1)Reaction of genipin and phenylhydrazine(obtained compound 3,4,5,6,7,8,9,10);(2)Reductive amination of genipin and primary amines(aniline,phenmethyl amine)in methanol solution,with NaBH₃CN as the reductant.Eleven compounds 11,12,13,14,15,16,17,18,19,20,21 were prepared);(3)Reductive amination of genipin and amino acid methyl ester in methanol solution, with NaBH₃CN as reductant.Compound 22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42 were obtained.Totally forty monoterpene alkaloid-like compounds prepared from genipin and amines were obtained.The chemical structures of thiry-four compounds among them were confirmed by NMR and MS.Most important work we did was the preparation of Huperzine A-genipin hybrids. Huperzine A is a very famous drug which was widely used to treat Alzheimer's disease and genipin can prevent the toxicity of Alzheimer's amyloidβ-protein in cultured hippocampal neurons.These two compounds both have neuroprotection activity.They were combined by reductive amination based on combinatorial chemistry.Three new Huperzine A-genipin hybrids were prepared.We hope to find more active compound from them to deal with Alzheimer's disease.Preliminary bioactivity tests of some products were performed.Compound 43 showed weak inhibitory activity against acetylcholine esterase.Some compounds like 4,11 and 17 exhibit antifungal activity.Their MID were 2.0,1.5 and 2.0μg respectively.