Design and synthesis of new coumarin hybrids with antiproliferative activity against neuroblastoma cells

In order to identify new agents with anticancer activity, our research project is aimed at the design and synthesis of new hybrid molecules using the fragment-based strategy. For this purpose, two naturally occurring scaffolds with antiproliferative and antioxidant properties, respectively, were combined. We synthesized new hydrazones of coumarin-3-carboxylic acid with aryloxy-substituted vanillin or isovanillin, obtaining a small library (16 compounds, throughout multistep synthesis. The antioxidant properties of the compounds, were evaluated on the basis of their chemical structure by using in vitro DPPH colorimetric assay 1. Furthermore, their anticancer activity was tested by MTT assay in a neuroblastoma (NB) cell line (HTLA-230) and in an etoposide-resistant one (HTLA-ER), selected by HTLA-230 2. Both the NB cell lines were treated for 48 h with increasing concentrations (2.5-30 μM) of the compounds. Most of the IC50 values showed an anticancer effect at low micromolar range (8-25 μM) with a similar trend in both NB cell populations. Based on these results, it is possible to highlight some structure-activity-relationships useful for designing new compounds with better antiproliferative activity. At the same time, further biological studies will be undertaken to identify the mechanisms of action of these new promising anticancer compounds. (1) Brand-Williams, W.; Cuvelier, M. E.; Berset, C. Use of a Free Radical Method to Evaluate Antioxidant Activity. LWT - Food Sci. Technol. 1995, 28 (1), 25–30. https://doi.org/10.1016/S0023-6438(95)80008-5. (2) Colla, R.; Izzotti, A.; De Ciucis, C.; Fenoglio, D.; Ravera, S.; Speciale, A.; Ricciarelli, R.; Furfaro, A. L.; Pulliero, A.; Passalacqua, M.; Traverso, N.; Pronzato, M. A.; Domenicotti, C.; Marengo, B. Glutathione- Mediated Antioxidant Response and Aerobic Metabolism: Two Crucial Factors Involved in Determining the Multi-Drug Resistance of High-Risk Neuroblastoma. Oncotarget 2016, 7 (43), 70715–70737. https://doi.org/10.18632/oncotarget.12209.