Dönmez Serhat, Lapinskaite Ringaile, Atalay Hazal Nazlican, Tokay Esra, Kockar Feray, Rycek Lukas, Özbil Mehmet, Tumer Tugba Boyunegmez
Graduate Program of Molecular Biology and Genetics, School of Graduate Studies, Canakkale Onsekiz Mart University, Canakkale 17020, Turkey.
Department of Organic Chemistry, Center for Physical Sciences and Technology (FTMC), Akademijos g. 7, Vilnius LT-08412, Lithuania.
ACS Bio Med Chem Au. 2024 Jul 26;4(4):178-189. doi: 10.1021/acsbiomedchemau.4c00027. eCollection 2024 Aug 21.
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, selectively inhibited the proliferation and migration of prostate cancer cells while exhibiting minimal effects on healthy cells. Furthermore, 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, 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 possesses the potential to serve as a dual topoisomerase inhibitor and can be further developed as a promising candidate for prostate cancer treatment.
多靶点药物的研发是癌症治疗的一种创新方法，旨在提高药物疗效同时将副作用降至最低。在此，我们试图阐明塞拉吉二苯甲酮B衍生物对癌细胞存活及双拓扑异构酶I/II酶活性的抑制作用。结果表明，在这些化合物中，[具体化合物名称1]选择性抑制前列腺癌细胞的增殖和迁移，而对健康细胞影响极小。此外，[具体化合物名称2]对拓扑异构酶表现出双重抑制作用。计算分析与酶抑制试验结果相符，证明该化合物与拓扑异构酶催化位点具有很强的结合亲和力。令我们惊讶的是，[具体化合物名称3]并未诱导前列腺癌细胞凋亡；相反，它诱导自噬基因表达和脂质过氧化，同时降低谷胱甘肽水平，这可能与铁死亡机制有关。总之，研究结果表明[具体化合物名称4]具有作为双重拓扑异构酶抑制剂的潜力，可进一步开发成为前列腺癌治疗的有前景候选药物。
