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.