Byrne Andrew J, Bright Sandra A, Fayne Darren, McKeown James P, McCabe Thomas, Twamley Brendan, Williams Clive, Meegan Mary J
School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152-160 Pearse St, Dublin 2, Trinity College Dublin, Ireland.
Med Chem. 2018 Feb 6;14(2):181-199. doi: 10.2174/1573406413666171002123907.
Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt's lymphoma (BL).
The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt's lymphoma (BL).
A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG- 75 (chemoresistant) to establish preliminary structure-activity relationships.
Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 µM and 0.47 µM in MUTU-1 cells and 1.41 µM and 1.92 µM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt's lymphoma cell lines MUTU-1 and DG-75.
This class of pharmaceutically active compounds with potential for the treatment of Burkitt`s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.
淋巴细胞癌（淋巴瘤）约占全球恶性疾病的12%。硝基苯乙烯支架被确定为开发针对伯基特淋巴瘤（BL）的特别有效化合物的主要目标结构。
本研究的目的是合成一组硝基苯乙烯化合物，并评估它们在伯基特淋巴瘤（BL）中的活性。
使用亨利-克诺文纳格尔缩合反应设计并合成了一组结构多样的化合物。单晶X射线分析证实了这些新结构的六个实例的E构型。还研究了一些与硝基苯乙烯相关的化合物，包括1,3-双（芳基）-2-硝基丙烯以及含有硝基乙烯药效团的杂环支架，如3-硝基-2-苯基-2H-色烯。使用BL细胞系EBV-MUTU-1和EBV+DG-75（化疗耐药）评估化合物的抗增殖活性以建立初步的构效关系。
成功建立了具有优化硝基苯乙烯支架和3-硝基-2-苯基-2H-色烯结构 的先导化合物，在MUTU-1细胞中的典型IC50值分别为0.45μM和0.47μM，在DG-75细胞中分别为1.41μM和1.92μM。细胞死亡机制被确定为凋亡，并且发现先导化合物在伯基特淋巴瘤细胞系MUTU-1和DG-75中引发与紫杉醇相当的凋亡作用。
这类具有治疗伯基特淋巴瘤潜力的药物活性化合物表明硝基苯乙烯类药物在化疗中具有潜在作用。
