三氮唑埃博霉素类似物的合成
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摘要
埃博霉素具有紫杉醇类似的生物活性，但是它们对多重耐药性的癌细胞有更好的活性。更重要的是它们对于一些拮抗紫杉醇的细胞系也有作用，此外还具有良好的水溶性以及相对简单的结构。为了探寻它们的SAR信息，以及寻找更多的具有活性的埃博霉素类似物，在世界范围内掀起了合成埃博霉素类化合物的热潮。
首先，在第二章介绍了大环上的12-13双键被三氮唑环取代的1,4-三氮唑埃博霉素类似物2-1。同样在该章研究了三氮唑埃博霉素似物2-1在碱金属作用下的裂解方式。
文献上报道了CuAAC反应产物1,4-三氮唑和线性药物分子中酰胺和双键相似，其对应的类似物保持了相当的生物性质。Chen和Kong最近报道了一种在生理条件或乙腈下纳米氧化亚铜催化的CuAAC反应。因此，为了探寻三氮唑模拟12-13双键的可能性以及评价纳米氧化亚铜构筑大环的效率，我们报道了通过纳米氧化亚酮催化下的click反应得到1,4-三氮唑埃博霉素类似物2-1。
通过Aldol反应，Horner-Wadsworth-Emmons反应，大环酯化以及点击反应等反应合成了1,4-三氮唑埃博霉素类似物。关键步骤是利用纳米氧化亚酮催化的1,3偶极环加成反应产生大环和三氮唑环。这是第一次评价纳米氧化亚酮在构筑大环分子的效率。较高的反应产率证明了纳米氧化亚铜是一种较好的分子内大环成环的催化剂。通过计算机模拟，X-单晶衍射，NMR等构象分析显示了C10-C14位的刚性和平面结构以及C1-C7位构象的变化导致了1,4-三氮唑埃博霉素类似物活性的丧失。我们使用傅立叶变换离子回旋共振质谱仪研究了化合物2-1在质子和碱金属辅助下的碰撞活化解离质谱。
其次，在第三章，一种新颖的1,5-三氮唑埃博霉素类似物3-1通过[Cp*RuCl]_4催化的1,3偶极环加成反应合成。计算机模拟表明了1,5三氮唑埃博霉素类似物3-1和天然产物埃博霉素A的结构相似度要比1,4三氮唑埃博霉素类似物2-1好许多。中间体3-2在[Cp*RuCl]_4催化下发生1,3-偶极环加成反应以41%的产率得到中间体3-19。三氮唑埃博霉素类似物3-1的生物活性正在研究中。
在第四章我们正在尝试将抗癌药物埃博霉素和人类急性髓细胞白血病的干细胞凋亡剂含笑内酯合并在一起做成杂合药物。而这种策略可能帮助我们发现更多具有生物活性的癌症干细胞凋亡剂。现在我致力于完成这个杂合药物并且已经成功得到两个关键的中间体。
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.
首先，在第二章介绍了大环上的12-13双键被三氮唑环取代的1,4-三氮唑埃博霉素类似物2-1。同样在该章研究了三氮唑埃博霉素似物2-1在碱金属作用下的裂解方式。
文献上报道了CuAAC反应产物1,4-三氮唑和线性药物分子中酰胺和双键相似，其对应的类似物保持了相当的生物性质。Chen和Kong最近报道了一种在生理条件或乙腈下纳米氧化亚铜催化的CuAAC反应。因此，为了探寻三氮唑模拟12-13双键的可能性以及评价纳米氧化亚铜构筑大环的效率，我们报道了通过纳米氧化亚酮催化下的click反应得到1,4-三氮唑埃博霉素类似物2-1。
通过Aldol反应，Horner-Wadsworth-Emmons反应，大环酯化以及点击反应等反应合成了1,4-三氮唑埃博霉素类似物。关键步骤是利用纳米氧化亚酮催化的1,3偶极环加成反应产生大环和三氮唑环。这是第一次评价纳米氧化亚酮在构筑大环分子的效率。较高的反应产率证明了纳米氧化亚铜是一种较好的分子内大环成环的催化剂。通过计算机模拟，X-单晶衍射，NMR等构象分析显示了C10-C14位的刚性和平面结构以及C1-C7位构象的变化导致了1,4-三氮唑埃博霉素类似物活性的丧失。我们使用傅立叶变换离子回旋共振质谱仪研究了化合物2-1在质子和碱金属辅助下的碰撞活化解离质谱。
其次，在第三章，一种新颖的1,5-三氮唑埃博霉素类似物3-1通过[Cp*RuCl]_4催化的1,3偶极环加成反应合成。计算机模拟表明了1,5三氮唑埃博霉素类似物3-1和天然产物埃博霉素A的结构相似度要比1,4三氮唑埃博霉素类似物2-1好许多。中间体3-2在[Cp*RuCl]_4催化下发生1,3-偶极环加成反应以41%的产率得到中间体3-19。三氮唑埃博霉素类似物3-1的生物活性正在研究中。
在第四章我们正在尝试将抗癌药物埃博霉素和人类急性髓细胞白血病的干细胞凋亡剂含笑内酯合并在一起做成杂合药物。而这种策略可能帮助我们发现更多具有生物活性的癌症干细胞凋亡剂。现在我致力于完成这个杂合药物并且已经成功得到两个关键的中间体。
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.
引文
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[1]Nicolaou K C, Sasmal P K, Reddy G R M V, et al. Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues. Angew. Chem. Int. Ed.,2003,42:3515-3520
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[1]Nicolaou K C, Sasmal P K, Reddy G R M V, et al. Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues. Angew. Chem. Int. Ed.,2003,42:3515-3520
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[1]Walsh J J, Coughlan D, Heneghan N, et al. A novel artemisinin-quinine hybrid with potent antimalarial activity. Bioorg. Med. Chem. Lett.,2007,17:3599-3602
[2]Tietze L F, Bell H P, Chandrasekhar S. Natural Product Hybrids as New Leads for Drug Discovery. Angew. Chem. Int. Ed.,2003,42:3996-3520
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[5]Schreiber S L. Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science,2000,287:1964-1969
[6]Castaneda-Acosta J, Fischer N H, Vargas D. Biomimetic Transformations of Parthenolide. J. Nat. Prod.,1993,56:90-98
[7]Glunz P W, He L, Danishefsky S J, et al. The synthesis and evaluation of12,13-benzodesoxyepothilone B:a highly convergent route. Tetrahedron Lett.,1999,40:6895-6898
[8]Nicolaou K C, Sasmal P K, Reddy G R M V, et al. Design, Synthesis, and Biological Properties of Highly Potent Epothilone B Analogues. Angew. Chem. Int. Ed.,2003,42:3515-3520
[9]Grandjean G, Boutonnier A, Guerreiro C, et al. On the Preparation of Carbohydrate-Protein Conjugates Using the Traceless Staudinger Ligation. J. Org. Chem.,2005,70:7123-7132
[10]Racherla U S, Brown H C. Chiral Synthesis via Organoboranes. Remarkably Rapid and Exceptionally Enantioselective (Approaching100%ee) Allylboration of Representative Aldehydes at-100℃under New Salt-Free Conditions. J. Org. Chem.,1991,56:401-414
[11]Teruhiko I, Toshiaki A, Eiko O, et al. Two-Directional Elaboration of Hydroxyacetone under Thermodynamically Controlled Conditions: Allylation or2-Propynylation and Aldol Reaction. J. Org. Chem.,2007,72:435-411