Uracil derivatives/ursolic acid hybrids - naturally derived compounds as anticancer agents

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 -CH₂- 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 IC₅₀ 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.