Synthesis, biological evaluation, and in silico studies of lantadene-derived pentacyclic triterpenoids as anticancer...

We report the anticancer activity, structure-activity relationships (SAR), molecular mechanism, and in silico docking studies of nine pentacyclic triterpenoids derived from lantadene A. The NCI-60 cytotoxicity screening of synthesized compounds on 60 human tumor cell lines, representing nine different cancers revealed that compound 6, bearing dual C-3 and C-22 butyryloxy substitutions at the pentacyclic triterpenoid scaffold, displays remarkable potency with mean growth inhibition of 98.7% at 10 μM. The SRB five-dose assay of compound 6 exhibited that it suppresses the growth of all NCI-60 cell lines with a GI₅₀ value in the single-digit micromolar range, except for one. The Western blot analysis revealed that compound 6 inhibits the expression of IKK-β and its down-stream effector NF-κB (p65). Molecular docking analysis of compound 6 with IKK-β showed hydrogen bond interactions with GLN425 and ARG427 and hydrophobic contact with PHE424 residues as the prominent interactions. Molecular dynamics simulation of the docked complex suggested that the complex was fairly stable. Compound 7, possessing the isobutyryloxy groups at the analogous positions of compound 6 was the second-favorable anticancer agent. Conversely, the substitution of the hydroxy group in compounds emerged as the least favorable substitution at both the C-3 and C-22 positions of the pharmacophore. The presence of the 22β-angeloyloxy side-chain, akin to the natural product lantadene A, exhibited moderate favorability for enhanced activity. As a whole, the cytotoxicity data of compounds underscores the preference for linear and extended substitutions at both the C-3 and C-22 positions of the pharmacophore for heightened activity.