通过Mizoroki-Heck反应和点击化学合成Oridonin衍生物的细胞毒性活性。,Anti-Cancer Agents in Medicinal Chemistry

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通过Mizoroki-Heck反应和点击化学合成Oridonin衍生物的细胞毒性活性。
Anti-Cancer Agents in Medicinal Chemistry ( IF 2.6 ) Pub Date : 2019-01-01 , DOI: 10.2174/1871520619666190118121439
Wei Hou ₁ , Qiuju Fan ₂ , Lin Su ₁ , Hongtao Xu ₃

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背景技术天然产物（NP）是在进化上选择的“特权结构”，其对抗癌药的发现和开发进展具有深远的影响。然而，由于繁琐而复杂的合成途径，基于NPs结构修饰的新药的寻找常常受到阻碍。幸运的是，即使存在可靠的功能，Mizoroki-Heck反应和铜催化的炔-叠氮化物环加成（CuAAC）仍可为NP选择性修饰提供完美的策略。目的在这里，我们使用oridonin（一种具有广泛生物活性的对映型月桂烷双萜类化合物）作为亲本分子来产生具有抗癌活性的类似物。方法基于冬凌草甲素的结构-活性关系研究，制备了冬凌草甲素的衍生物，并通过Mizoroki-Heck反应和CuAAC合成。评价了新冬凌草甲素衍生物对癌细胞和正常细胞的细胞毒性。此外，通过流式细胞术和蛋白质印迹分析评估了所选有效类似物的凋亡作用和细胞周期阻滞作用。结果分别通过Heck反应和铜催化的炔-叠氮化物环加成反应（CuAAC）获得了两种新的冬凌草甲素的C-14和C-17修饰衍生物。体外抗增殖活性表明，引入C-14（2-三唑）乙酰氧基部分可以保留或增强细胞毒性，而引入C-17苯环可能发挥负面作用。进一步的研究表明，衍生物23具有广谱抗增殖活性，有效克服了耐药性，并且对非癌细胞具有弱的细胞毒性。初步的机理研究表明，23可能导致G2 / M期停滞并诱导PC-3细胞凋亡。结论Mizoroki-Heck反应和CuAAC是复杂天然产物结构修饰的理想策略。引入C-14（2-三唑）乙酰氧基部分可以保留或增强冬凌草甲素的细胞毒性，引入C-17苯基可以对其细胞毒性产生负面影响。初步的机理研究表明，23可能导致G2 / M期停滞并诱导PC-3细胞凋亡。结论Mizoroki-Heck反应和CuAAC是复杂天然产物结构修饰的理想策略。引入C-14（2-三唑）乙酰氧基部分可以保留或增强冬凌草甲素的细胞毒性，引入C-17苯基可以对其细胞毒性产生负面影响。初步的机理研究表明，23可能导致G2 / M期停滞并诱导PC-3细胞凋亡。结论Mizoroki-Heck反应和CuAAC是复杂天然产物结构修饰的理想策略。引入C-14（2-三唑）乙酰氧基部分可以保留或增强冬凌草甲素的细胞毒性，引入C-17苯基可以对其细胞毒性产生负面影响。

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Synthesis of Oridonin Derivatives via Mizoroki-Heck Reaction and Click Chemistry for Cytotoxic Activity.

BACKGROUND Natural products (NPs) are evolutionarily chosen "privileged structures" that have a profound impact upon the anticancer drug discovery and development progress. However, the search for new drugs based on structure modification of NPs has often been hindered due to the tedious and complicated synthetic pathways. Fortunately, Mizoroki-Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC) could provide perfect strategies for selective modification on NPs even in the presence of liable functionalities. OBJECTIVE Here, we used oridonin, an ent-kaurane diterpenoid that showed a wide range of biological activities, as a parent molecule for the generation of analogues with anticancer activity. METHODS Derivatives of oridonin were generated based on the structure-activity relationship study of oridonin and synthesized via Mizoroki-Heck reaction and CuAAC. The cytotoxicity of new oridonin derivatives were evaluated on both cancer cells and normal cells. Furthermore, the apoptotic effect and cell cycle arrest effect of the selected potent analogue were evaluated by flow cytometry and western blotting analysis. RESULTS Two series of novel C-14 and C-17 modified derivatives of oridonin were obtained via Heck reaction and copper-catalyzed alkyne-azide cycloaddition (CuAAC), respectively. In vitro antiproliferative activities showed that the introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance cytotoxicity, whereas the introduction of C-17 phenyl ring might exert negative effect. Further studies demonstrated that derivative 23 exhibited broad-spectrum antiproliferative activity, effectively overcame drug-resistance and showed weak cytotoxicity on non-cancer cells. Preliminary mechanistic studies indicated that 23 might cause G2/M phase arrest and induce apoptosis in PC-3 cells. CONCLUSION Mizoroki-Heck reaction and CuAAC are perfect strategies for structure modification of complex natural products. The introduction of C-14 (2-triazole)acetoxyl- moiety could retain or enhance the cytotoxicity of oridonin, the introduction of C-17 phenyl group might exert negative effect on its cytotoxicity.

更新日期：2019-11-01

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