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

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

Volume: 14 Issue: 2

Author(s): Andrew J. Byrne, Sandra A. Bright, Darren Fayne, James P. McKeown, Thomas McCabe, Brendan Twamley, Clive Williams and Mary J. Meegan*

Affiliation:

• School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2,Ireland

Keywords: Anticancer agent, B cell, Burkitt's lymphoma, DG-75, MUTU-1, 3-Nitro-2-pheny-2H-chromene, nitrostyrene.

Abstract: 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-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.

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.

Cite this article as:

Byrne J. Andrew, Bright A. Sandra , Fayne Darren , McKeown P. James , McCabe Thomas, Twamley Brendan, Williams Clive and Meegan J. Mary*, Synthesis, Antiproliferative and Pro-Apoptotic Effects of Nitrostyrenes and Related Compounds in Burkitt's Lymphoma, Medicinal Chemistry 2018; 14 (2) . https://dx.doi.org/10.2174/1573406413666171002123907