Dissertation > Excellent graduate degree dissertation topics show

The Synthesis of Triazole-Epothione Analogues

Author: DuanXiZuo
Tutor: LuoGuoAn
School: Nankai University
Course: Chemical Biology
Keywords: Triazole-epothilone analogue 1,3-DipolarCycloaddition Cu2O-NPs [Cp*RuCl]4 CAD
CLC: TQ463
Type: PhD thesis
Year: 2012
Downloads: 5
Quote: 0
Read: Download Dissertation

Abstract


Epothilone has similar biological activity to taxol, but they are more active against multi-drug-resistant cells. Moreover, it has been recognized that epothilones are effective against a number of Taxol-resistant tumor cell lines. Besides, it has better water solubility and far simpler structure than taxane. A worldwild effort to synthesize the epothilone class of molecules, and to get more detailed SAR studies and search more specific and higher activity epothilone derivatives.Firstly, the Triazole-epothilone analogue2-1which the12-13olefine was replaced by triazole ring was introduced in the charpter2. The effects of alkali metal ion cationization on fragmentation pathways of Triazole-epothilone analogue2-1was also investigated in this charpter.The CuAAC product-1,4-triazole, was reported to be isostatic to amides and olefins in drugs with linear structure, and the resulted analogues maintain significant biological activity. Chen and Kong recently reported the use of Cu2O nanoparticles (Cu2O-NPs) to catalyze CuAAC reaction either under physiological conditions or in acetonitrile. Thus, to explore the possibility to mimic the olefin at C12-C13position and evaluate the efficiency of Cu2O-NP for cyclization of large ring, here we report the synthesis of1,4Triazole-Epothilone analogue2-1with Cu2ONP catalyzed click reaction.The1,4-Triazole-epothilone analogues was synthesized by aldol reaction, Horner-Wadsworth-Emmons reaction, macrolactonization and click reaction. The key step to generate the macrocyclic ring and the triazole ring is to apply Cu2O Nanoparticles (Cu2O-NP) catalyzed1,3-Dipolar Cycloaddition. This is the first time to evaluate the efficiency of Cu2O-NP for cyclization of large ring. The superior yield of this reaction demonstrates that the Cu2O-NP is a feasible catalyst for intramolecular macrocyclic ring formation. Conformational analysis with computational modeling, X-ray crystallography and NMR studies showed that rigid and planar conformation on region C10-C14and the conformational change on region C1-C7is probably vital to epothilone’s biological activity. The collisionally activated dissociation mass spectra of the protonated and alkali metal cationized ions of1,4triazole-epothilone analogue2-1were studied in a Fourier transform ion cyclotron resonance mass spectrometer.Then, in charpter3, a novel type of1,5-Triazole-epothilone analogue3-1was synthesized by1,3-Dipolar Cycloaddition which catalyzed by [Cp*RuCl]4. The computational modeling suggested the conformation of1,5-triazole epothilone analogue3-1is much more similar as natural epothilone A than1,4-Trizaole epothilone analogue2-1. Exposure of the key intermediate3-2to catalyst system [Cp*RuCl]4provided cyclization product3-19in41%yield. The bioactivity of1,5-triazole epothilone3-1is being under invertigation. In the charpter4, we are trying to combine anti-cancer drug epothilone and human acute myelogenous leukemia stem and progenitor cells apoptosis agent into a hybrid drug4-1. This strategy may help us to find more cancer stem apoptosis agents with significant biological activity. I am currently working on synthesizing this novel hybrid drug and two key intermediates were obtained.

Related Dissertations

  1. Parametric Technology in Apparel Pattern-Making Based on Constraint Graph,TS941.2
  2. Research of Core Technologies in the Software of Color Digital Jacquard,TP391.41
  3. The Research and Design of CAD for Cam Based on VB,TH112.2
  4. CAD/CAPP/CAM Integrated System Development for Key Components in Marine Diesel,U664.121
  5. Research on Grading Technology of Pleat Complex Structure Apparel,TS941.2
  6. Research and Application on Post Processing for Five-Axis CNC Machining Center,TG659
  7. The Comparative Research of Clothing Stencil CAD,TS941.2
  8. Research on Feature Extraction, Selection and Classification Algorithms for Pulmonary CAD,TP391.41
  9. The System for Engineering Drawing Vectoring and 3D Reconstruction,TP391.41
  10. Research on 3d Hierarchically Parametric Design Method,TP391.72
  11. Research on Display Optimization of 2D-CAD by Multi-line Simplification,TP391.72
  12. The Standard Part Intelligent Design System for Automobile Panel Mould under the Unigraphic Platform,TP391.72
  13. The Research of Parameterization Modeling System of the Individual 3D Dress Human Body Based on the Characteristics,TP391.41
  14. Research on Simulation of Loop Pile Tufted Carpet Base on Open Inventor,TS106.76
  15. Research on the Light-Weight Optimization of Disc Brake Structure Based on CAD/CAE Technique,U463.512
  16. Research on CAD/CAM Integrated System of Reticulated Structures,TU399
  17. Computer Aided Design for 19m Sightseeing Ship,U662.9
  18. Study on Key Technology for CAD of Lost Foam Mould,TP391.72
  19. Design and Development of a CAD/FEA Seamless Integration Platform CAFIP,TP391.72
  20. Jeans garment CAD design and rapid generation of a model,TS941.2
  21. Interactive local constraints fabric texture mapping technology research and implementation,TP391.41

CLC: > Industrial Technology > Chemical Industry > Pharmaceutical chemical industry > Production of organic compounds in drug
© 2012 www.DissertationTopic.Net  Mobile