The development of multitargeted drugs represents an innovative approach to cancer treatment, aiming to enhance drug effectiveness while minimizing side effects. Herein, we sought to elucidate the inhibitory effect of selagibenzophenone B derivatives on the survival of cancer cells and dual topoisomerase I/II enzyme activity. Results demonstrated that among the compounds, SelB-1 selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, SelB-1 showed a dual inhibitory effect on topoisomerases. Computational analyses mirrored the results from enzyme inhibition assays, demonstrating the compound's strong binding affinity to the catalytic sites of the topoisomerases. To our surprise, SelB-1 did not induce apoptosis in prostate cancer cells; instead, it induced autophagic gene expression and lipid peroxidation while reducing GSH levels, which might be associated with ferroptotic death mechanisms. To summarize, the findings suggest that SelB-1 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.

Department of Molecular Biology and Genetics Faculty of Science Canakkale Onsekiz Mart University Canakkale 17020 Turkey

Department of Molecular Biology and Genetics Faculty of Sciences and Arts Balikesir University Balikesir 10145 Turkey

Department of Organic Chemistry Center for Physical Sciences and Technology Akademijos g 7 Vilnius LT 08412 Lithuania

Department of Organic Chemistry Faculty of Science Charles University Hlavova 8 128 43 Praha 2 Czechia

Graduate Program of Molecular Biology and Genetics School of Graduate Studies Canakkale Onsekiz Mart University Canakkale 17020 Turkey

Institute of Biotechnology Gebze Technical University Kocaeli 41400 Turkey

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Synthesis of Selaginpulvilin D by [2 + 2 + 2] Cyclotrimerization─A Second-Generation Approach