Synthesis and Identification of New 4-Arylidene Curcumin Analogues as Potential Anticancer Agents Targeting Nuclear Factor-KB Signaling Pathway

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, China.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 11/2010; 53(23). DOI: 10.1021/jm1004545
Source: PubMed


A series of curcumin analogues including new 4-arylidene curcumin analogues (4-arylidene-1,7-bisarylhepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogues can effectively decrease the growth of a panel of lung cancer cells at submicromolar and low micromolar concentrations. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogues exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogues also reduced the tumorigenic potential of cancer cells in a clonogenic assay.

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    • "Selection and preparation of data set Marvin Sketch 5.12.01 was used to draw the structures of the 29 '4-arylidene curcumin analogues' in 2D (mol2) format. The inhibitory activity (IC50) values of these analogues were taken from the literature reported by Qiu et al. (2010) and converted into their logarithmic pIC50 values. The model generation and its analysis was performed using "
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    ABSTRACT: NF-κB transcription factor plays a vital role in the protection of transformed cells from apoptosis, thus resulting in the onset/progression of cancer. Activation of NF-κB is strictly controlled by IκB kinase, and therefore IκB kinase inhibition forms the basis for anticancer drug research. We present here a novel fragment-based QSAR model using 4-arylidene curcumin analogues having IκB kinase inhibitory properties. The insights into the contribution of each chemical fragment of the analogues in IκB kinase inhibitory activity were used to generate a combinatorial library containing 167,828 molecules and their inhibitory activities were predicted by the reported G-QSAR model. We report top two scoring compounds BEP and BHP possessing high docking scores of −9.21 and −8.98 kcal/mol, respectively. Molecular dynamics simulations studies showed that the trajectories of the IκB kinase complexed with BEP and BHP were stable over a considerably long time period (16 ns). The two compounds reported here showed high binding affinity and stability with IκB kinase and thus can be taken forward as promising anticancer leads. The G-QSAR model reported here will pave way for the development of novel leads by high-throughput activity prediction of similar compounds.
    Full-text · Article · May 2015 · Medicinal Chemistry Research
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    • "This in turn leads to a substantial increase (60%) in intensity of redox potential with a slightly decreased potential value, 0.62 V for pyrazole curcumin. This is in good agreement with our previously reported results on the anti-oxidant properties of curcumin pyrazole [23]. A substituent in the aromatic ring attached to pyrazole is expected to influence the stability of the phenoxyl radical which in turn should perturb the redox behavior of the resulting compound. "
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    ABSTRACT: Here, we report studies on the antioxidant activity and redox behavior of curcumin and its structurally modified synthetic analogues. We have synthesized a number of analogues of curcumin which abrogate its keto-enol tautomerism or substitute the methylene group at the centre of its heptadione moiety implicated in the hydride transfer and studied their redox property. From cyclic voltammetric studies, it is demonstrated that H- atom transfer from CH2 group at the center of the heptadione link also plays an important role in the antioxidant properties of curcumin along with that of its phenolic–OH group. In addition, we also show that the conversion of 1, 3- dicarbonyl moiety of curcumin to an isosteric heterocycle as in pyrazole curcumin, which decreases its rotational freedom, leads to an improvement of its redox properties as well as its antioxidant activity
    Full-text · Article · Jan 2015 · Electrochimica Acta
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    • "The procedure used for the synthesis of T83 was described previously [19]. Generally, an amount of 1.0 mmol of 1, 3-diketones curcumin analogs [20] and 2 mmol of the corresponding benzaldehyde as well as 25 mL toluene were added to a three-neck rounded flask equipped with a water dispenser. "
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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus--associated malignancy that is most common in East Asia, Africa, and Alaska. Radiotherapy is the main treatment option; unfortunately, disease response to concurrent radiotherapy and chemotherapy varies among patients with NPC, and in many cases, NPC becomes resistant to radiotherapy. Our previous studies indicated that Jab1/CSN5 was overexpressed and plays a role in the pathogenesis and radiotherapy resistance in NPC. Therefore, it is important to seek for innovative therapeutics targeting Jab1/CSN5 for NPC. In this study, we explored the antitumor effect of a curcumin analogue T83 in NPC, and found T83 exhibits antitumor activity and induces radiosensitivity through inactivation of Jab1 in NPC. NPC cell viability and proliferation were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell cycle distribution was detected with use of flow cytometry. Apoptosis was examined by using the Annexin V/propidium iodide staining assay and cleavage poly(ADP-ribose polymerase (PARP) and cleavage caspase-3 expression. Jab1 expression was examined by Western blotting. A growth inhibitory effect was observed with T83 treatment in a dose- and time-dependent manner. T83 significantly induced G2/M arrest and apoptosis in NPC. In addition, T83 inhibited Jab1 expression and sensitized NPC cells to radiotherapy. Our data indicate that T83 exhibits potent inhibitory activity in NPC cells and induces radiotherapy sensitivity. Thus, T83 has translational potential as a chemopreventive or therapeutic agent for NPC.
    Full-text · Article · Jul 2013 · BMC Cancer
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