Construction And Preliminary Bioactive Evaluation Of Monoterpenoid Alkaloids Based On Secologanin

Secologanin,one of the most important small molecules in the family of iridoids,harbors diverse chemical properties and serves as a key precursor for the biosynthesis of more than 2000 monoterpenoid alkaloids.Numerous monoterpenoid alkaloids provide a rich source of medicinal products with a wide spectrum of biological activities.However,it is difficult to sythesize them via traditional chemical way due to the structure complexicity of multiple cycles and oftenly multi-chiral centers.Driven by its inherient highly reactive functional group and active transformation in the natural organisms,it is an effecient strategy to prepare an immense range of structurally complex new monoterpenoid alkaloids with potential new biological activities by either biomimetic synthesis or quick chemical method based on secologanin.Our research work mainly focused on biomimetic synthesis,chemo-enzymatic preparation and chemical way to build diversified novel non-natural monoterpenoid alkaloids and found new topoisomerase Ⅰ inhibitors and antimalaries based on structure manipulation of secologanin which can be divided into three parts as follows.(1)Biomimetic synthesis of tetrahydroangutstines derived from secologanin and their inhibitory activity evaluation against topoisomerase Ⅰ.Secologanin was utilized as the original substrate by strictosidine synthase to biomimetically generate 21 N-substituted(S)-3,14,18,19-tetrahydroangutstine derivatives.The following biological tests showed that these alkaloids were novel topoisomerase Ⅰ inhibitors and exhibited antiproliferative activity.Structure-activity relationship study suggested that N-(2-Cl benzoyl)substituted derivative(2.7i)was the most potent compound which was then used to study and show the possible binding mode of this molecule with a Topl-DNA covalent complex via molecular dynamics simulations.(2)Chemo-enzymatic preparation of azepino-indole alkaloids derived from secologanin and the discovery of antimalarial compound.Secologanin was stereoselevtively condensated with our newly designed 2-(1H-indol-4-yl)-ethanamine substrate to gererate a pair of enantiomers of azepino-indolyl strictosidines,in which the strictosidine synthase afforded the S-configured product and the phosphate buffer resulted in the R-configured one.Following efficient chemo-enzymactic manipulation on the azepino-indolyl strictosidines provided five non-natural azepino-indole alkaloids.Biological activity assays suggested that two alkaloids(a pair of epimers,3.8 and 3.11)with new skeleton showed moderate antimalarial activity.(3)Asymmetric construction of monoterpenoid alkaloids derived from secologanin.Secologanin harbors several very reactive functional groups and chiral centers,making itself highly active for chemical derivitization.Thus,secologanin was employed as a synthon to systematically and enantioselectively build a non-natural monoterpenoid alkaloid libraries(totally 56 compounds)with abundant several structural skeletons.By analyzing the structural characteristics of secologanin,a key biosynthetic synthon in monoterpenoid alkaloids,we rapidly and efficiently constructed varieties of polycyclic and multi-chiral monoterpenoid alkaloids with structural diversity and discovered new tetrahydroangutstines as topoisomerase Ⅰ inhibitors and azepino-indole alkaloids with antimalarial activity.These findings further strengthen the strategy to efficiently build and disclose non-natural potential bioactive monoterpenoid alkaloids utilizing secologanin,the natural biosynthetic precursor of monoterpenoid alkaloids,as the core starting material.