Design and synthesis of new Thieno[2,3-d]pyrimidine-based derivatives as anti-breast cancer: Biological evaluation, PIM-1 kinase inhibition, and in silico studies

IF 4.7 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-09-16 DOI:10.1016/j.bioorg.2025.109003

Menna Tallah M. Sayed , Zeinab Mahmoud , Makarem M. Said , Amr M. Abdou , Rasha A. Hassan

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Abstract

This study primarily aimed to develop and evaluate new thieno[2,3-d]pyrimidine derivatives with potential anticancer properties through a comprehensive process of design and synthesis. Using a variety of spectroscopic methods, the chemicals produced were thoroughly analyzed. The cytotoxic effects of the derivatives on the MCF-7 breast cancer cell line were examined. Compound 15 demonstrated the strongest anticancer activity, with IC₅₀ value of 34.49 ± 1.32 μM, compared to doxorubicin (IC₅₀ = 34.20 ± 0.28 μM). The most potent derivatives were assessed for their ability to suppress PIM-1 kinase activity. PIM-1 inhibitory activity of compounds 8, 12, 15, and 17 was evaluated compared to staurosporine. The results showed potent to moderate activity with IC₅₀ values of 0.771 ± 0.028, 1.332 ± 0.049, 0.212 ± 0.008, and 2.66 ± 0.099 μM, respectively, and IC₅₀ = 0.47 ± 0.017 μM for staurosporine. Moreover, a scratch wound healing assay revealed that compound 15 significantly impeded cell migration. Additionally, compound 15 displayed a marked increase in Bax expression by 2.35-fold and caspase-3 levels by 1.12-fold in MCF-7 breast cancer cell line. On the other hand, it caused a downregulation of Bcl-2 level by 0.31-fold. Additionally, the binding relationships produced between compound 15 and the PIM-1 kinase active site were investigated using molecular docking experiments, providing insights into their inhibitory potential. Finally, to further assess the stability of the compound 15-PIM-1 kinase complex and validate the docking results, molecular dynamics (MD) simulations were performed.

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新型Thieno[2,3-d]嘧啶衍生物抗乳腺癌的设计和合成：生物学评价，PIM-1激酶抑制，和硅研究。

本研究主要旨在通过设计和合成的综合过程，开发和评价具有潜在抗癌特性的新型噻吩[2,3-d]嘧啶衍生物。利用各种光谱方法，对所产生的化学物质进行了彻底的分析。研究了其衍生物对MCF-7乳腺癌细胞株的细胞毒作用。化合物15的抗癌活性最强，IC50值为34.49±1.32 μM，而阿霉素的IC50值为34.20±0.28 μM。最有效的衍生物被评估其抑制PIM-1激酶活性的能力。比较了化合物8、12、15和17与staurosporine的PIM-1抑制活性。结果表明，staurosporine的IC50值分别为0.771±0.028、1.332±0.049、0.212±0.008和2.66±0.099 μM， IC50值为0.47±0.017 μM。此外，抓伤愈合实验显示，化合物15显著阻碍细胞迁移。此外，化合物15在MCF-7乳腺癌细胞系中Bax表达量显著增加2.35倍，caspase-3表达量显著增加1.12倍。另一方面，使Bcl-2水平下调0.31倍。此外，利用分子对接实验研究了化合物15与PIM-1激酶活性位点之间的结合关系，从而深入了解了它们的抑制潜力。最后，为了进一步评估化合物15-PIM-1激酶复合物的稳定性并验证对接结果，进行了分子动力学（MD）模拟。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.