New Dimethoxyaryl-Sesquiterpene Derivatives with Cytotoxic Activity Against MCF-7 Breast Cancer Cells: From Synthesis to Topoisomerase I/II Inhibition and Cell Death Mechanism Studies Araque, Ileana Vergara, Rut Mella, Jaime Aránguiz, Pablo Espinoza-Catalán, Luis Salas, Cristian O. Fernández Barrero, Alejandro Quílez Del Moral, José Francisco Villena, Joan Cuellar, Mauricio aryl-sesquiterpenes Cytotoxic activity Apoptosis MCF-7 cells Topoisomerases I/II In silico studies This research was funded by FONDECYT (Fondo Nacional de Desarrollo Científico y Tecnológico, grant number N◦ 1201395) to M.C.F. The APC was funded by Universidad Central de Chile to M.V.V. This work as supported by MINISTERIO de CIENCIA e INNOVACIÓN, PID2019- 106222RBC32/SRA (State Research Agency, 10.13039/501100011033) Breast cancer is a prevalent type of cancer worldwide, leading to both high incidence and mortality, and hence, effective and safe drugs are needed. Because of this, the use of natural products and their derivatives has become a popular strategy for developing new chemotherapeutic agents. In this study, 17 new sesquiterpene-aryl derivatives were synthesized using (−)-drimenol as the starting material. The cytotoxicity of these semi-synthetic derivatives was determined in MCF-7 cells, a breast cancer model, and in a non-tumor cell line, MCF-10, to evaluate selectivity. The results show that five of these sesquiterpene derivatives had IC50 values between 9.0 and 25 µM. Of these, compound 14c stands out for its higher cytotoxicity in MCF-7 cells but lower cytotoxicity in MCF-10 cells, being more selective than daunorubicin (selective index values of 44 and 28, respectively). In addition, compound 14c induced oxidative stress in MCF-7 cells, activated caspases-3/7, and selectively inhibited topoisomerase II (TOP2) versus topoisomerase I (TOP1) in MCF-7 cells. In silico studies allowed us to propose a binding mode for 14c to the TOP2 DNA complex to validate the experimental results. Therefore, this study demonstrated the importance of aryl-sesquiterpene structures and their promising profiles in the search for new bioinspired antitumor drugs in natural products. 2025-07-01T08:51:05Z 2025-07-01T08:51:05Z 2025-05-09 journal article Araque, I.; Vergara, R.; Mella, J.; Aránguiz, P.; Espinoza-Catalán, L.; Salas, C.O.; Barrero, A.F.; Quílez del Moral, J.; Villena, J.; Cuellar, M.A. New Dimethoxyaryl-Sesquiterpene Derivatives with Cytotoxic Activity Against MCF-7 Breast Cancer Cells: From Synthesis to Topoisomerase I/II Inhibition and Cell Death Mechanism Studies. Int. J. Mol. Sci. 2025, 26, 4539. [DOI: 10.3390/ijms26104539] https://hdl.handle.net/10481/105002 10.3390/ijms26104539 eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional MDPI