Lucie Rárová

Cardiac glycosides, traditionally used for heart failure, are increasingly recognized for their anticancer potential. This study evaluated the in vitro antitumor activity of ten cardiac glycoside derivatives on androgen-insensitive (DU-145) and androgen-sensitive (LNCaP) prostate cancer cells, utilizing non-tumorigenic RWPE-1 cells as a control. Key assays included cell viability, proliferation, cell cycle distribution, apoptosis, and nuclear steroid receptor analysis. Among the tested series, compound 10, an oleandrigenin-derived androstane, exhibited the most significant therapeutic potential. It demonstrated pronounced effects on cell viability, proliferation, and apoptosis, while significantly altering molecular pathways and receptor dynamics specifically in prostate cancer cells. Crucially, compound 10 exhibited preferential cytotoxicity toward prostate cancer cells compared with non-tumorigenic RWPE-1 cells. It modulated AR signaling by reducing AR expression, nuclear localization, and transcriptional activity, while largely preserving ER-α and ER-β expression. Together with its effects on cell-cycle progression and apoptosis, these findings support 10 as a lead structure for further investigation in prostate cancer.

A series of more than 20 new amides of oleanolic acid and ursolic acid with selected aromatic amines were synthesized, and the structures of all compounds were analyzed and elucidated. Moreover, the compounds were subjected to the cytotoxicity assays in four cancer cell lines (CCRF-CEM, MCF7, HeLa, and G-361), using normal human fibroblasts (BJ) as reference cells for determining the toxicity of the investigated compounds. The 1,10-phenanthroline derivatives 4a, 4b, 5a, and 5b showed the highest cytotoxicity in all four cancer cell lines, but they were comparably toxic in human fibroblasts. The most promising results were achieved with 14a and 14b showing high cytotoxicity in the cancer cell lines and no toxicity in human fibroblasts. They were subjected to the investigation of the in vitro cell apoptosis, resulting in a confirmation of activation of apoptotic pathways in the CCRF-CEM cell line. The structure–activity relationships were documented by the cytotoxicity of 14a vs. 16a, and of 14b vs 16b, showing reverse effects in CCRF-CEM and MCF7 cancer cell lines. To investigate nanoassembly, initial screening of the target compounds by ultraviolet (UV) spectrometry was performed. Compounds 9b, 13b, 16b, and 17b, soluble both in methanol and in water, were selected for a more detailed investigation by transmission electron microscopy (TEM) microscopy and were found to form spherical nanoassemblies, frequently interconnected in small agglomerates and/or loose networks, while the other target compounds of this series showed no nanoassembling based on the TEM imaging. For each investigated compound, the nanoassemblies formed in methanol were substantially bigger than those formed in water.

Correction for ‘Atropisomeric 1-phenylbenzimidazoles affecting microtubule organization: influence of axial chirality’ by Jana Pospíšilová et al. , Org. Biomol. Chem. , 2024, https://doi.org/10.1039/d4ob00863d.

Benzimidazoles are frequently used in medicinal chemistry. Their anticancer effect is among the most prominent biological activities exhibited by this scaffold. Although numerous benzimidazole derivatives have been synthesized, possible atropisomerism of ortho-substituted 1-phenylbenzimidazoles has been largely overlooked. The aim of this research was to synthesize a small library of novel atropisomeric benzimidazole derivatives and explore their biological activity in various cancer and normal human cell lines. The new unique structural motif provides an interesting 3D architecture with axial chirality, which further contributes to molecular complexity and specificity. Racemates and their separated atropisomers arrested the cell cycle, caused apoptosis, and affected microtubule organization in cancer cells in vitro at different intensities. Moreover, this phenomenon was also verified by the inhibition of endothelial cell migration. These results showed that (+)-atropisomers, especially 5n, exhibit a stronger effect and show promise as agents for cancer therapy.

α-Tocopheryl succinate (α-TS) and α-tocopheryloxyacetic acid (α-TEA) are potent inducers of apoptosis in cancer cells and efficient suppressors of tumors in experimental model cancer cell lines. They exhibit selective cytotoxicity against tumor cells and very limited or no toxicity toward nonmalignant cells. In the present work, a series of new α-tocopherol derivatives were synthesized as analogs of α-TS and α-TEA. The cytotoxic activity of obtained compounds was tested using three human cancer cell lines, including chronic lymphoblastic leukemia (CEM), breast adenocarcinoma (MCF7), cervical adenocarcinoma (HeLa), and normal human fibroblasts (BJ). The introduction of an alkyl substituent into the ether-linked acetic acid moiety in α-TEA increased anticancer activity. α-Tocopheryloxy-2-methylpropanoic acid with two additional geminal methyl groups was more active against CEM cells compared to α-TEA and non-toxic to normal cells. In order to acquire a deeper understanding of the biological activity of synthesized compounds, a molecular docking study was also conducted. Our research confirmed that vitamin E derivatives are interesting and valuable compounds in terms of their potential therapeutic use as anticancer agents.

A chemoselective procedure for MCPBA oxidation of 26-thiodiosgenin to corresponding sulfoxides and sulfone was elaborated. An unusual equilibration of sulfoxides in solution was observed. Moreover, α-alkylation of sulfoxide and sulfone was investigated. Finally, the biological activity of obtained compounds was examined.