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

Abstract

A series of curcumin analogues including new 4-arylidene curcumin analogs (4-arylidene-1,7-bisaryl-hepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogs can effectively decrease the growth of a panel of lung cancer cells in sub- and low micromolar concentration ranges. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogs 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 analogs also reduced the tumorigenic potential of cancer cells in a clonogenic assay.

Deubiquitinase Inhibition of 19S Regulatory Particles by 4-Arylidene Curcumin Analog AC17 Causes NF-κB Inhibition and p53 Reactivation in Human Lung Cancer Cells

“…S1). As we have previously described, IKK blockage by 4-arylidene curcumin analogs only partly reveals the mechanism of the anticancer activity of AC17 (22). Although the exact mode of action of AC17 remains unclear, AC17 most likely is a pleiotropic molecule such as curcumin, which modulates numerous targets (24)(25)(26).…”

“…4-Arylidene curcumin analog AC17, (1E,6E)-1,7-bis(3,4-dimethoxyphenyl)-4-(4-hydroxy-3-methoxybenzylidene) hepta-1,6-diene-3,5-dione), was synthesized in an analogous manner as previously reported (22). Other reagents were obtained from the following sources: TNFa, NEM (N-ethylmaleimide), MG-132, Nutlin-3a, and dimethyl sulfoxide (DMSO; Sigma); Ub-AMC (ubiquitin-7-amido-4-methylcoumarin), human 19S proteasome, human 20S proteasome, human 26S proteasome, Suc-LLVY-AMC, and Z-LLE-AMC (BostonBiochem); Z-ARR-AMC (Calbiochem); and Vectors (pRL-TK and pNF-kB-luc; Promega).…”

“…AC17, a 4-arylidene curcumin analog, was initially synthesized and identified as an inhibitory kB (IkB) kinase (IKK) inhibitor in our preliminary study (22). Compared with the parent compound curcumin, AC17 shows improved oral bioavailability, metabolic stability (23), and moderately potent anticancer activities against several different cancer cell lines, including lung cancer, colon cancer, breast cancer, and hepatocellular carcinoma cells ( Supplementary Fig.…”

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

“…The compounds exhibited selectivity against colon carcinoma cells which could be ascribed to their high lipophilicity that favors a greater and faster cellular uptake and thereby overcoming their apparently higher instability under physiological condition. Qiu et al [92] have synthesized a series of new 4-arylidene curcumin analogs which inhibited growth of a panel of lung cancer cells at sub-micromolar concentrations. Compounds 117-126 were found to exert superior growth inhibitory activities against A549 Cells through NF-B inhibition which can be explained, at least, in part by inhibition of I B phosphorylation and degradation via IKK blockage.…”

Rapid synthesis of curcuminoid pyrazoles with antiviral effects through one-pot combinatorial modification of total curcuminoids

“…14 Structural modification of curcumin has received attention worldwide and led to a number of bioactive curcumin derivatives. [15][16][17][18][19] Among these derivatives, curcumin pyrazoles were found to show antimicrobial 20 and antitumor activities. 21,22 CNB-001, a pyrazole derivative of curcumin, was reported to exhibit neurotrophic activity, which can be used for the treatment of Parkinson's Disease and ischemic stroke.…”