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

Abstract

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) values in the nanomolar range (GI = 0.02-0.99 μM). Lead compound 7h exhibited EC 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-κB pathway. In TMD-231 breast cancer cells, treatment with 7h reduced DNA binding activity of NF-κB through inhibition of IKK-β mediated p65 phosphorylation and caused elevation of basal IκBα levels through inhibition of constitutive IκBα turnover and NF-κB activation. Molecular docking and dynamic modeling studies indicated that 7h interacts with the kinase domain of the monomeric IKKβ subunit, leading to inhibition of IKKβ activation, and compromising phosphorylation of downstream targets of the NF-κB pathway; dynamic modeling studies show that this interaction also causes unwinding of the α-helix of the NEMO binding site on IKKβ. Molecular docking studies with 10, a water-soluble analog of 7h, demonstrate that this analog interacts with the dimerization/oligomerization domain of monomeric IKKβ and may inhibit oligomer formation and subsequent autophosphorylation. Sesquiterpene lactones 7h and 10 are considered ideal candidates for potential clinical development.

Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

“…The structures of SARS-CoV-2 proteins used in this study were retrieved from I-TASSER (neural networkbased structure predictions) [9]. Proteins were preprocessed using the Protein Preparation Wizard module of Schrödinger's Prime module by the MMGBSA method, using molecular mechanics, the generalized Born solvent model, and solvent accessibility [18][19][20].…”

“…Unbiased or whole-protein docking was conducted using AutoDock-Vina molecular docking package [18,23,24]. Briefly, proteins and drugs were prepared in Vina format prior to docking.…”

“…Briefly, proteins and drugs were prepared in Vina format prior to docking. Unlike targeted docking protocols, the docking box was constructed to include the entire protein structure [18]. Drugs were then docked against each protein of interest using the Raccoon2 graphical user interface for Vina [25].…”

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…3), was effective and potent against several cancer cell lines including leukaemia (GI 50 = 0.10-0.23 µM), colon (GI 50 = 0.14-1.17 µM), melanoma (GI 50 = 0.15-1.47 µM), renal (GI 50 = 0.02-0.70 µM), ovarian (GI 50 = 0.15-1.86 µM), prostate (GI 50 = 0.72-0.83 µM), and breast (GI 50 = 0.17-1.03 µM) cancer cell line subpanels. 46 Further investigation indicated that triazole compound 2 was a potent inhibitor of nuclear factor (NF)-kB and cell proliferation in TMD-231 (MDA-MB-231) cell line. Moreover, treatment of TMD-231 cells with derivative 2 decreased the DNA binding activity of NF-kB by inhibiting p65 phosphorylation mediated by inhibitor of NF-kB kinase (IKK)-b and increasing basal IkBα levels via inhibition of substantial NF-kB activation and IkBα turnover.…”

Computational Target-Based Drug Repurposing of Elbasvir, an Antiviral Drug Predicted to Bind Multiple SARS-CoV-2 Proteins

“…The system was next equilibrated using the NPT protocol (constant number of particles, pressure and temperature) with default temperature (300 o K) and pressure (1 bar). MD simulations were then conducted for 100-200 ns using Desmond's GPU-based simulation method [18][19][20][21][22]. Results were analyzed using the Simulation Interactions Diagram module from Schrödinger Maestro.…”