MMB triazole analogs are potent NF-kappa B inhibitors and anti-cancer agents against both hematological and solid tumor cells

摘要

Triazole derivatives of melampomagnolide B (MMB) have been synthesized via click chemistry methodologies and screened against a panel of 60 human cancer cell lines. Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI(50)) values in the nanomolar range (GI(50) = 0.02-0.99 mu M). Lead compound 7h exhibited EC50 values of 400 nM and 700 nM, respectively, against two AML clinical specimens. Compound 7h was significantly more potent than parthenolide as an inhibitor of p65 phosphorylation in both hematological and solid tumor cell lines, indicating its ability to inhibit the NF-kappa B pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-kappa B through inhibition of IKK-beta mediated p65 phosphorylation and caused elevation of basal I kappa B alpha levels through inhibition of constitutive I kappa B alpha turnover and NF-kappa B activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKK beta subunit, leading to inhibition of IKK beta activation, and compromising phosphorylation of downstream targets of the NF-kappa B pathway; dynamic modeling studies show that this interaction also causes unwinding of the alpha-helix of the NEMO binding site on IKK beta. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKK beta and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development. (C) 2018 Elsevier Masson SAS. All rights reserved.