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
Year: 2025
Type: article
Abstract: 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.
DOI: 10.3390/ijms26104539
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
Awards: G1855990336, G3690828678, G512381852, G5421974903, G6138190794, G7767928050, DRIMANIC SESQUITERPENES AND LICHENS METABOLITES AS A BUILDING BLOCK FOR THE SYNTHESIS OF NEW SESQUTERPEN-ORCINOL DERIVATIVES AS POTENTIAL TOPOISOMERASE I/II AND/OR PDK1 KINASE INHIBITORS., ACTUALIZACION DE COMPONENTES ELECTRONICOS Y SOFTWARE DE PROCESAMIENTO PARA ESPECTROMETRO DE RESONANCIA MAGNETICA NUCLEAR. FORTALECIMIENTO DE LA INVESTIGACION EN AREAS DE LA QUIMICA Y CIENCIAS AFINES.
OpenAlex ID: W4410240786