Semisynthesis of Novel Alicyclic Triterpene-Triazole Derivatives from <i>Boswellia sacra</i> 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 <i>in vitro</i> and <i>in silico</i> evaluations of 24 new alicyclic triterpene amide-containing 1<i>H</i>-1,2,3-triazole derivatives (<b>4</b>, <b>5</b>, <b>7a</b>-<b>7k</b> and <b>8a</b>-<b>8k</b>). 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 <b>4</b>. 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 (<b>7b</b>-<b>7i</b>) exhibited greater antiproliferative activities than the β-KBA (<b>2</b>) used as a reference compound. Compound <b>7f</b> demonstrated noteworthy activity even at lower concentrations. In contrast, compounds <b>8a</b> and <b>8k</b> demonstrated relatively lower effects, being compared with parent compound <b>2</b>. Furthermore, compound <b>7f</b> 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 (<b>7b</b>-<b>7i</b>) 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 <b>2</b> and the amide linker and triazole moiety in the binding of these compounds.