Chlorine containing tetrahydropyrimidines: Synthesis, characterization, anticancer activity and mechanism of action.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-12-01 Epub Date: 2024-10-23 DOI:10.1016/j.bioorg.2024.107907

Emilija Milović, Ivana Z Matić, Nina Petrović, Ivana Pašić, Tatjana Stanojković, Miloš R Petrović, Goran A Bogdanović, Ferda Ari, Nenad Janković

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Abstract

The aim of the presented research was to explore anticancer potential of eleven newly synthesized tetrahydropyrimidine derivatives. The compounds were synthesized via Biginelli multicomponent one-pot reaction using different derivatives of vanillin, ethyl 4-chloroacetoacetate and (N-methyl)urea. The cytotoxic effects of the compounds were examined on three human malignant cell lines (HeLa, K562, and MCF7), and normal lung fibroblasts MRC-5. The mechanisms of anticancer activity were examined for two compounds 4a and 4b which showed the strongest and selective cytotoxicity against chronic myelogenous leukaemia K562 cells (IC₅₀ = 1.76 ± 0.09, and 1.66 ± 0.05, respectively). The changes of matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were investigated in the K562 cell line, as well as oncomiRNA miR-10b, miR-23a described to have both features, depending on a specific type of malignancy, and miR-34a with mostly described as a tumour suppressor.

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含氯四氢嘧啶：合成、表征、抗癌活性和作用机理。

本研究旨在探索十一种新合成的四氢嘧啶衍生物的抗癌潜力。这些化合物是利用香兰素、4-氯乙酰乙酸乙酯和（N-甲基）脲的不同衍生物通过 Biginelli 多组分一锅反应合成的。研究人员考察了这些化合物对三种人类恶性细胞系（HeLa、K562 和 MCF7）以及正常肺成纤维细胞 MRC-5 的细胞毒性作用。其中，4a 和 4b 对慢性骨髓性白血病 K562 细胞具有最强的选择性细胞毒性（IC50 分别为 1.76 ± 0.09 和 1.66 ± 0.05）。研究了基质金属蛋白酶 2 (MMP2)、基质金属蛋白酶 9 (MMP9) 和血管内皮生长因子 A (VEGFA) 在 K562 细胞系中的变化，以及 oncomiRNA miR-10b、miR-23a（根据特定的恶性肿瘤类型，被描述为具有两种特征）和 miR-34a （主要被描述为肿瘤抑制因子）的变化。

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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.