MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells.
MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells.
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DOI：
10.1016/j.ejmech.2018.08.010
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发表时间：
2018-09-05
影响因子：
6.7
通讯作者：
Crooks PA
中科院分区：
文献类型：
--
作者：
Janganati V;Ponder J;Balasubramaniam M;Bhat-Nakshatri P;Bar EE;Nakshatri H;Jordan CT;Crooks PA
通过点击化学方法合成了美拉波镁素B（MMB）的三唑衍生物，并针对一组60种人癌细胞系进行了筛选。几种衍生物显示出有希望的抗癌活性，提供纳摩尔范围内的生长抑制（GI 50）值（GI 50 = 0.02-0.99 μM）。先导化合物7 h对两种AML临床标本的EC 50值分别为400 nM和700 nM。在血液和实体瘤细胞系中，化合物7 h作为p65磷酸化抑制剂的效力显著高于小白菊，表明其抑制NF-κB途径的能力。在TMD-231乳腺癌细胞中，7 h处理通过抑制IKK-β介导的p65磷酸化降低NF-κB的DNA结合活性，并通过抑制组成性IκBα转换和NF-κB激活引起基础IκBα水平升高。分子对接和动力学模型研究表明，7 h与单体IKKβ亚基的激酶结构域相互作用，导致IKKβ活化抑制，并损害NF-κB通路下游靶点的磷酸化;动力学模型研究表明，这种相互作用还导致IKKβ上NEMO结合位点的α-螺旋解旋。与7 h的水溶性类似物10的分子对接研究表明，该类似物与单体IKKβ的二聚化/寡聚化结构域相互作用，并可能抑制寡聚体形成和随后的自磷酸化。倍半萜内酯7 h和10被认为是潜在临床开发的理想候选物。
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 analogue 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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影响因子：
20.3
作者：
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通讯作者：
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