Semisynthesis of novel alicyclic triterpene-triazole derivatives from Boswellia sacra gum resin : potential anti-breast cancer and immunomodulatory effects on T‑cell activation

In this current work, we report on the design, synthesis, cytotoxicity of new compounds, molecular docking studies, and in vitro and in silico evaluations of 24 new alicyclic triterpene amide-containing 1H-1,2,3-triazole derivatives (4, 5, 7a-7k and 8a–8k). All new compounds were characterized by 1H-, 13C-, 19F-NMR, and HR-ESI-MS spectroscopic techniques. X-ray crystallography unambiguously confirmed the exact structure of 4. The antibreast cancer activity of all compounds was evaluated against two prominent human breast and one normal cancer cell lines with IC50 values ranging from 352.31 to 61.47 μM (MDA-MB-231), 386.61 to 67.02 μM (MCF-7), and 445.37 to 103.41 μM (HDF), respectively. Eight derivatives (7b–7i) exhibited greater antiproliferative activities than the β-KBA (2) used as a reference compound. Compound 7f demonstrated noteworthy activity even at lower concentrations. In contrast, compounds 8a and 8k demonstrated relatively lower effects, being compared with parent compound 2. Furthermore, compound 7f significantly expanded CD4+ CD8- helper T cell population at both 5 and 10 μM concentrations, increasing the expression of PD-1 and TIGIT immune checkpoints at 5 μM. The binding modes of the most active hits (7b–7i) were deduced by in silico docking using cyclin-dependent kinase 4 (CDK4) as a prominent target. The molecular docking studies demonstrated appreciable binding interactions and docking scores of compounds at CDK-4 ligand binding site and a significant role for −OH in compound 2 and the amide linker and triazole moiety in the binding of these compounds.