Enhanced G-Quadruplex Stability and Anticancer Activity of N2-Aryl Deoxyguanosine-Modified T40214 Oligonucleotides Targeting STAT3 in Prostate Cancer.

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Nishant Kumar Choudhary, Swrajit Nath Sharma, Gourav Das, Atanu Ghosh, Siddharam Shivappa Bagale, Surajit Sinha, Kiran R Gore
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引用次数: 0

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a key molecular target in many cancers due to its role in tumor cell proliferation and survival. T40214, a G-quadruplex (G4) forming oligonucleotide, targets the Stat3 dimer and inhibits its DNA binding activity. In this study, we introduced N2-furfuryl and N2-cinnamyl deoxyguanosine modifications at the G-tetrad positions in T40214 to assess their structural and antitumor effects in prostate cancer cells. A single N2-furfuryl/cinnamyl modification preserved the stable parallel G4 conformation. Incorporating either of these modifications into the top G-quartet (TF15 and TC15) significantly enhanced thermal stability. Molecular dynamics simulation studies revealed that the aryl moieties were well accommodated at the 5'-ends without disrupting the interaction with Stat3. It is also evident that H-bonding and π-π stacking interactions induced due to the presence of the aryl moieties contributed to the improved thermal stabilities for TF15 and TC15, respectively. Gel mobility assays confirmed that all aryl-modified T40214 G4s form stable 5'-5' dimers, similar to native T40214. TF15 and TC15 derivatives exhibited potent antiproliferative activity (IC50 = 0.37-0.39 μM) and effectively induced apoptosis while suppressing the Stat3-mediated gene expressions in DU145 cells. Overall, these findings demonstrate the potential of these aryl modifications in T40214 as a promising Stat3-targeting therapeutic approach for prostate cancers.

n2 -芳基脱氧鸟苷修饰的靶向STAT3的T40214寡核苷酸在前列腺癌中增强g -四重体稳定性和抗癌活性
信号换能器和转录激活因子3 (Stat3)因其在肿瘤细胞增殖和存活中的作用而成为许多癌症的关键分子靶点。T40214是一种g -四重体(G4)形成的寡核苷酸,靶向Stat3二聚体并抑制其DNA结合活性。在这项研究中,我们在T40214的g -四聚体位置引入n2 -糠酰基和n2 -肉桂酰基脱氧鸟苷修饰,以评估它们在前列腺癌细胞中的结构和抗肿瘤作用。单一的n2 -糠基/肉桂基修饰保持了稳定的平行G4构象。在顶级g -四重奏(TF15和TC15)中加入这两种修饰都显著提高了热稳定性。分子动力学模拟研究表明,在不破坏与Stat3相互作用的情况下,芳基部分在5'端被很好地调节。此外,由于芳基基团的存在而诱导的h键和π-π堆叠相互作用也分别有助于提高TF15和TC15的热稳定性。凝胶迁移率实验证实,所有芳基修饰的T40214 G4s形成稳定的5‘-5’二聚体,与天然T40214相似。TF15和TC15衍生物具有较强的抗增殖活性(IC50 = 0.37 ~ 0.39 μM),能有效诱导DU145细胞凋亡,同时抑制stat3介导的基因表达。总的来说,这些发现证明了T40214中这些芳基修饰作为一种有希望的stat3靶向前列腺癌治疗方法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biochemistry Biochemistry
Biochemistry Biochemistry 生物-生化与分子生物学
CiteScore
5.50
自引率
3.40%
发文量
336
审稿时长
1-2 weeks
期刊介绍: Biochemistry provides an international forum for publishing exceptional, rigorous, high-impact research across all of biological chemistry. This broad scope includes studies on the chemical, physical, mechanistic, and/or structural basis of biological or cell function, and encompasses the fields of chemical biology, synthetic biology, disease biology, cell biology, nucleic acid biology, neuroscience, structural biology, and biophysics. In addition to traditional Research Articles, Biochemistry also publishes Communications, Viewpoints, and Perspectives, as well as From the Bench articles that report new methods of particular interest to the biological chemistry community.
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