Cyclodextrin / Inclusion Behavior Of Natural Medicine; Aza-fused Ring Indole And Aryl Enamine Ketone / Ester Synthesis And Biological Activity Study

The fascinating property enables cyclodextrins (CDs) to be successfully utilized as drug carriers. Cyclodextrins have a hydrophobic central cavity and can encapsulate drug molecules to form host-guest complexes or supramolecular species. This usually enhances and improves the water solubility and bioavailability of the encapsulated natural drugs in pharmaceutical industry. Therefore, it is of importance to study the complex behavior for natural products with cyclodextrin.Diazaheterocycle-fused indole and enamine ketones/esters derivatives are commonly found in nature and medicine molecules exist as this kind of scaffold. Because of their value as synthetic precursors for pharmaceutical compounds and broad range of biological activities, the synthesis of these compounds have received increasing interest over many years in organic chemistry and medicinal chemistry. Therefore, it is significant to study the synthesis of diazaheterocycle-fused indole and enamine ketones/esters derivatives.This thesis describes studies towards the inclusion complexation behavior, binding ability, characterization and solubilization effect of cyclodextrins (CDs) with two natural drugs (nimbin and taxifolin). At the same time, the cyclocondensation and substitution reactions for enamine ketones/esters were studied in this thesis. A number of novel 1,3-diazaheterocycle fused [1,2-a]indole derivatives and 2-aryl-substituted enamine ketones/esters were prepared by concise synthetic routes and the bioactivities of some compounds were evaluated.This thesis is composed of five chapters.In Chapters 1, a review of the preparation, characterization and their applications of the cyclodextrin complexes was presented. The complex behaviors for the typical natural drugs with cyclodextrins in recent years were presented.In Chapters 2, the inclusion complexation behavior, characterization and binding ability of nimbin withβ-cyclodextrin (β-CD) and its derivatives have been investigated in both solution and the solid state by means of XRD, DSC,1H and 2D NMR and UV-vis spectroscopy. The results showed that the water solubility of nimbin was obviously increased after resulting inclusion complex with cyclodextrins (Scheme 1).In Chapters 3, the preparation and characterization of water-soluble inclusion complexes formed by taxifolin with cyclodextrins (α-CD,β-CD andγ-CD) and its derivatives (2-hydroxypropyl-β-cyclodextrin, HPβCD) was researched. The binding ability, characterization and solubilization effect of taxifolin with CDs were studied (Scheme 2).In Chapters 4, a novel procedure for the facile synthesis of 1,3-diazaheterocycle-fused [1,2-a]indole derivatives was developed. By simply refluxing a reaction mixture of different types of heterocyclic ketene aminals (HKAs) and 1,4-benzoquinones catalyzed by AcOH, a novel library of 1,3-diazaheterocycle-fused [1,2-a]indoles was obtained (Scheme 3).In Chapters 5, a concise, efficient and environmental process for synthesis of 2-aryl-substituted enamine ketones/esters was developed under solvent-free conditions. By this method, a number of 2-aryl-substituted enamine ketones/esters were prepared and their bioactivities (antitumor and antibacterial activities) were evaluated. Several compounds were displayed potent biological activities (Scheme 4).