Diversity-Orientied Synthesis And α-Glucosidase Inhibition Of Natural-Like Mero-Sesquiterpenoids

The chemical diversity of natural products and their derivatives provides a huge contribution for developing novel drugs or lead compounds.However,the difficulty in collecting novel scaffolds possessing privileged moieties has recently declined in pharmaceutical research due to elaborate isolation procedures or lengthy total synthesis.Thus it is urgently required to improve the diversity of natural products and their derivatives.In this regard,diversity-oriented synthesis（DOS）has emerged recently as an efficient strategy for constructing complex and diverse molecules from simple precursors due to its avoiding too many total synthesis steps.Easily accessible NPs as starting scaffolds is particularly effective for constructing chemically diverse libraries that are useful for screening out potential lead compounds.In this thesis,we took the natural meroterpenes from Guava（Psidium guajava）as a template.The easily accessibleβ-caryophyllene and natural privileged moieties（lawsone,phloroglucin,and syncarpic acid）were selected as starting points to construct complex meroterpene-like library via simple derivation,transannular rearrangement or cycloaddition reactions.A diverse library containing 36 new natural-like meroterpenes was acquired.Their chemical structures including stereo configurations were determined unambiguously by NMR,HR-MS,CD and X-Ray data.Since the Guava fruits and leaves are popular food possessing hypoglycemic function,we screened all of the synthetic products for inhibiting againstα-glucosidase.The compounds 19、26、36、38、42 and 43 were found potential inhibitions with IC₅₀ ranging from 3.56 to 9.19μM which are obviously better than those of genistein(IC₅₀ 17.46μM)and the drug compound acarbose(IC₅₀>50μM).A further study on the enzyme kinetics showed those inhibitors posing mixture type inhibition on the target protein.The interactions between the high potential inhibitors and biomacromolecule were furtherly simulated by molecular docking analysis.