Michalak Olga, Cybulski Marcin, Kubiszewski Marek, Finiuk Nataliya, Kozak Yuliia, Milenkovic Dejan, Żurawicka Sylwia, Roszczenko Piotr, Bielawska Anna, Trzaskowski Bartosz, Gornowicz Agnieszka
Chemistry Section; Pharmacy, Cosmetic Chemistry and Biotechnology Research Group, Łukasiewicz Research Network-Industrial Chemistry Institute, 8 Rydygiera Str, Warsaw, 01-793, Poland.
Analytical Research Section, Pharmaceutical Analysis Laboratory, Łukasiewicz Research Network-Industrial Chemistry Institute, 8 Rydygiera Str, Warsaw, 01-793, Poland.
Sci Rep. 2025 Aug 6;15(1):28803. doi: 10.1038/s41598-025-14351-y.
A series of new uracil derivatives/ursolic acid hybrids were designed and synthesised as potential cytotoxic agents. The uracil, thymine, 6-methyluracil and 2-thiouracil moieties were linked to ursolic acid (1) through alkyl chains of different lengths (either four or six -CH- units). The cytotoxic activity of the synthesised conjugates was determined using the hormone-dependent breast cancer cell line MCF-7, the triple-negative breast cancer (TNBC) cell line MDA-MB-231 and normal cell lines: human skin fibroblasts (CCD-25Sk) and human bronchial epithelium (BEAS-2B). The five compounds, 4a, 5a, 6a, 7a and 9a, exhibited a significant reduction in the cell viability of human BC cell lines. Analog 6a, which demonstrated high cytotoxic activity against MCF-7 and MDA-MB-231 cell lines with IC values of 14.00 µM and 5.83 µM, respectively, was also antitumorigenic in all biochemical assays. It increased p53 and Bax levels in MDA-MB-231 cells as well as significantly decreased Akt kinase levels in the tested cells, and effectively inhibited collagen biosynthesis. Finally, for the selected compounds, we computationally predicted their ADME properties and performed molecular docking to Akt protein kinase. The results of computational docking indicated that the preferred binding mode for all of them was the inactive form of Akt kinase, as in the case with known Akt allosteric inhibitors.
设计并合成了一系列新型尿嘧啶衍生物/熊果酸杂化物作为潜在的细胞毒性剂。尿嘧啶、胸腺嘧啶、6-甲基尿嘧啶和2-硫尿嘧啶部分通过不同长度的烷基链（四个或六个-CH-单元）与熊果酸（1）相连。使用激素依赖性乳腺癌细胞系MCF-7、三阴性乳腺癌（TNBC）细胞系MDA-MB-231以及正常细胞系：人皮肤成纤维细胞（CCD-25Sk）和人支气管上皮细胞（BEAS-2B）测定合成缀合物的细胞毒性活性。化合物4a、5a、6a、7a和9a对人乳腺癌细胞系的细胞活力有显著降低。类似物6a对MCF-7和MDA-MB-231细胞系表现出高细胞毒性活性，IC值分别为14.00 μM和5.83 μM，在所有生化测定中也具有抗肿瘤作用。它增加了MDA-MB-231细胞中p53和Bax的水平，同时显著降低了测试细胞中Akt激酶的水平，并有效抑制了胶原蛋白的生物合成。最后，对于选定的化合物，我们通过计算预测了它们的ADME性质，并对Akt蛋白激酶进行了分子对接。计算对接结果表明，与已知的Akt变构抑制剂情况一样，它们所有的优选结合模式都是Akt激酶的无活性形式。
