Synthesis, molecular docking, and saturation-transfer difference NMR spectroscopy of longipinane derivatives as novel microtubule stabilizers

Five new and three known longipinane derivatives were obtained and their molecular interactions with α,β-tubulin were evaluated using in vitro and in silico assays. Alkaline hydrolysis of the natural longipinane diester 3, isolated in high yields from the roots of Stevia serrata, gave (3R,4S,5S,7S,8R,9S,10R,11R)-longipinan-7,8,9-triol-1-one (1). Compounds 1 and 3 were the starting materials for the preparation of esters 2, 4–8 derived from acetic, angelic, benzoic, cinnamic, and 4-fluorocinnamic acids. It was found that the presence of cinnamate groups on the longipinane framework of 5–8 accelerated tubulin polymerization, while (3R,4S,5S,7S,8S,9S,10R,11R)-7,8-dicinnamoyloxy-9-hydroxylongipinan-1-one (5) also induced significant microtubule stabilization. Molecular docking studies revealed that 5 (Edock = −9.88 kcal/mol) interacts at the paclitaxel binding site of tubulin, suggesting that this could be the mechanism for producing microtubule stability, while saturation-transfer difference NMR spectroscopy experimentally confirmed that 5 binds to tubulin. [Display omitted] •Several longipinanes bearing unsaturated and/or aromatic esters were synthesized.•Some longipinane esters modified the tubulin polymerization/depolymerization process.•Longipinane derivatives containing cinnamate ester residues stabilize microtubules.•Docking analyses show that longipinane cinnamates bind to the paclitaxel binding site.•STD-NMR spectra confirmed contact between tubulin and longipinantriolone dicinnamate.