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

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 (GI50) values in the nanomolar range (GI50 = 0.0...

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Veröffentlicht in:European journal of medicinal chemistry 2018-09, Vol.157, p.562-581
Hauptverfasser: Janganati, Venumadhav, Ponder, Jessica, Balasubramaniam, Meenakshisundaram, Bhat-Nakshatri, Poornima, Bar, Eli E., Nakshatri, Harikrishna, Jordan, Craig T., Crooks, Peter A.
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container_title European journal of medicinal chemistry
container_volume 157
creator Janganati, Venumadhav
Ponder, Jessica
Balasubramaniam, Meenakshisundaram
Bhat-Nakshatri, Poornima
Bar, Eli E.
Nakshatri, Harikrishna
Jordan, Craig T.
Crooks, Peter A.
description 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 (GI50) values in the nanomolar range (GI50 = 0.02–0.99 μM). 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-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. [Display omitted] •Design and synthesis of triazole derivatives of melampomagnolide B (MMB).•Screening of MMB triazoles against hematological and solid tumor cell lines.•MMB triazole inhibition of p65 and IκBα phosphorylation, and NF-κB binding to DNA.•Structural modeling of interaction of MMB triazoles with the IKKβ protein subunit.
doi_str_mv 10.1016/j.ejmech.2018.08.010
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Several derivatives showed promising anti-cancer activity, affording growth inhibition (GI50) values in the nanomolar range (GI50 = 0.02–0.99 μM). 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-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. 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source MEDLINE; Elsevier ScienceDirect Journals Complete
subjects Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Proliferation - drug effects
Click chemistry
Dose-Response Relationship, Drug
Humans
Leukemia cell lines
Melampomagnolide B
Models, Molecular
Molecular Structure
NF-kappa B - antagonists & inhibitors
NF-kappa B - metabolism
NF-κB pathway
Phosphorylation - drug effects
Sesquiterpenes - chemistry
Sesquiterpenes - pharmacology
Structure-Activity Relationship
Triazole derivatives
Triazoles - chemistry
Triazoles - pharmacology
title MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells
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