Design, synthesis, and biological evaluation of novel <strong>EF24 </strong>and <strong>EF31 </strong>analogs as potential I&kappa;B kinase &beta; inhibitors for the treatment of pancreatic cancer

Abstract

Given the important role that inhibitory kappa B (IκB) kinase β (IKKβ) plays in pancreatic cancer (PC) development and progression, inhibitors targeting IKKβ are believed to be increasingly popular as novel anti-PC therapies. Two synthetic molecules, named EF24 and EF31, exhibited favorable potential in terms of inhibition of both IKKβ activity and PC cell proliferation. Aiming to enhance their cellular efficacy and to analyze their structure–activity relationship, four series of EF24 and EF31 analogs were designed and synthesized. Through kinase activity and vitality screening of cancer cells, D6 displayed excellent inhibition of both IKKβ activity and PC cell proliferation. Additionally, multiple biological evaluations showed that D6 was directly bound to IKKβ and significantly suppressed the activation of the IKKβ/nuclear factor κB pathway induced by tumor necrosis factor-α, as well as effectively inducing cancer cell apoptosis. Moreover, molecular docking and molecular dynamics simulation analysis indicated that the dominant force between D6 and IKKβ comprised hydrophobic interactions. In conclusion, D6 may be a promising therapeutic agent for PC treatment and it also provides a structural lead for the design of novel IKKβ inhibitors.

Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases

“…Later they optimized this formula as “lipidated Cur” which can achieve more than 5 μM in the brains of mice [ 106 , 107 ]. We have been working with this formula and found significant beneficial effects both in vivo and in vitro models of AD [ 108 ], and in an in vitro model of glioblastoma [ 14 ].…”

“…Cur can inhibit the inflammatory cytokines, including IL1, IL6, TNF-α, IFN-γ, and COX-2 activity [ 152 ]. Several studies have demonstrated that Cur can inhibit activated astrocytes and microglia, as shown by reducing GFAP and Iba-1 levels [ 108 , 153 ] ( Figure 17 ). Therefore, as an anti-inflammatory natural polyphenol, Cur is a promising compound for tackling oxidative stress and inflammation in AD.…”

“…However, when administered orally, achieving therapeutically significant concentrations of Cur outside the GI-tract is practically impossible because of its poor bioavailability. However, the Cur bioavailability in animal models of AD [ 12 , 13 , 108 ] and HD [ 40 ] following i.p. or oral administration was about 250–350 nM in the brain tissue.…”

Bioactivities of EF24, a Novel Curcumin Analog: A Review

“…Wu et al synthesized and purified 20 EF24 analogs, from which they identified one to have greater activity than EF24, showing potent anti-migration and anti-proliferative activity against A549 cells (89). Xie et al designed and synthesized four series of EF24 analogs, from which they found one displaying excellent inhibition of both IKKβ activity and pancreatic cancer (PC) development and progression (90). A group from Germany synthesized 14 EF24 analogs and revealed that they have promising anti-proliferative activity against eight cancer cell lines with low IC 50 values, and showed superior anti-angiogenic and vascular-disruptive effects (91).…”

<p>Emodin Reverses Gemcitabine Resistance of Pancreatic Cancer Cell Lines Through Inhibition of IKKβ/NF-κB Signaling Pathway</p>

“…[16][17][18] Curcumin and its analogs EF24 and EF31 are also toxic, and there are huge defects in drug metabolism. [19][20][21] Therefore, finding a new type of IKKβ/NF-κB inhibitor with high efficiency and low toxicity, and exploring if it can reverse the resistance of gemcitabine has become our main research goal.…”