The Synthesis Of Triazole-Epothione Analogues

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.