Selagibenzophenone B and Its Derivatives: SelB-1, a Dual Topoisomerase I/II Inhibitor Identified through In Vitro and In Silico Analyses

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Serhat Dönmez, Ringaile Lapinskaite, Hazal Nazlican Atalay, Esra Tokay, Feray Kockar, Lukas Rycek, Mehmet Özbil, Tugba Boyunegmez Tumer
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Abstract

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.

Abstract Image

Selagibenzophenone B 及其衍生物:通过体外和硅学分析发现的拓扑异构酶 I/II 双重抑制剂 SelB-1
开发多靶点药物是治疗癌症的一种创新方法,旨在提高药物疗效的同时最大限度地减少副作用。在此,我们试图阐明硒二苯甲酮 B 衍生物对癌细胞存活和 I/II 双拓扑异构酶活性的抑制作用。结果表明,在这些化合物中,SelB-1 能选择性地抑制前列腺癌细胞的增殖和迁移,而对健康细胞的影响则微乎其微。此外,SelB-1 对拓扑异构酶具有双重抑制作用。计算分析反映了酶抑制实验的结果,证明该化合物与拓扑异构酶的催化位点有很强的结合亲和力。令我们惊讶的是,SelB-1 并没有诱导前列腺癌细胞凋亡;相反,它诱导了自噬基因表达和脂质过氧化,同时降低了 GSH 水平,这可能与铁凋亡机制有关。总之,研究结果表明,SelB-1具有作为双重拓扑异构酶抑制剂的潜力,可进一步开发为治疗前列腺癌的候选药物。
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来源期刊
ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
发文量
0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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