Synthesis, Antiproliferative and Pro-Apoptotic Effects of Nitrostyrenes and Related Compounds in Burkitt's Lymphoma

被引:7
作者
Byrne, Andrew J. [1 ]
Bright, Sandra A. [2 ]
Fayne, Darren [2 ]
McKeown, James P. [1 ]
McCabe, Thomas [3 ]
Twamley, Brendan [3 ]
Williams, Clive [2 ]
Meegan, Mary J. [1 ]
机构
[1] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Pharm & Pharmaceut Sci, 152-160 Pearse St, Dublin 2, Ireland
[2] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, 152-160 Pearse St, Dublin 2, Ireland
[3] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Chem, Dublin, Ireland
关键词
Anticancer agent; B cell; Burkitt's lymphoma; DG-75; MUTU-1; 3-Nitro-2-pheny-2H-chromene; nitrostyrene; IN-VITRO CYTOTOXICITY; BETA-NITROSTYRENES; TYROSINE KINASE; CANCER-CELLS; DERIVATIVES; INHIBITORS; AGENTS; 3-NITROQUINOLINES; 3-AMINOFLAVONES; 1,2,3-TRIAZOLES;
D O I
10.2174/1573406413666171002123907
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Background: 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). Objectives: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt's lymphoma (BL). Methods: 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. Results: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2H-chromene structures were successfully established with typical IC50 values of 0.45 mu M and 0.47 mu M in MUTU-1 cells and 1.41 mu M and 1.92 mu M, 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. Conclusion: 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.
引用
收藏
页码:181 / 199
页数:19
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