Abstract
A series of novel C15 urushiol derivatives were designed by introducing a pechmann structure and F-, Cl-, and Br-nitro substituents with different electronic properties into its alkyl side chain, as well as a triazolyl functional group in its aromatic oxide. Their chemical structures were determined based on the analysis of the NMR (nuclear magnetic resonance) spectroscopic and mass spectrometric data. The results showed that compound 4 exhibited a strong inhibition of the HepG2 cell proliferation (half maximal inhibitory concentration (IC50): 2.833 μM to human hepatocellular carcinoma (HepG2), and 80.905 μM to human normal hepatocytes (LO2)). Furthermore, it had an excellent synergistic effect with levopimaric acid. The nitrogen atom of the triazole ring formed a hydrogen-bonding interaction with Gly103, Gly154, and Tyr308, which made compound 4 bind to histone deacetylase (HDAC)2 more tightly. One triazole ring and His33 formed a π–π stacking effect; the other, whose branches were deep into the pocket, further enhanced the interaction with HDAC2. Meanwhile, compound 4 involved a hydrophobic interaction with the residues Phe210 and Leu276. The hydrophobic interaction and π–π stacking provided powerful van der Waals forces for the compounds.
Highlights
An increasing number of anti-tumor drugs are being derived from plants
Novel urushiol derivatives have an anti-platelet agglutination activity. They markedly reduce the levels of TNF-α and IL-1β [14], as well as the anti-tumor virus in liver, lung, and breast cancer, by preventing tumor cell proliferation and inducing tumor cell differentiation [15,16,17,18], in addition to the degree of alcohol-induced steatosis; they contribute to improving the immune capacity and potentially treat alcoholic liver disease (ALD) [19]
Our research results have suggested that the binding pattern of urushiol derivative ligands such as ligand compound 4 to the HDAC2 receptor [23,24] could be detected by the molecular docking technique
Summary
An increasing number of anti-tumor drugs are being derived from plants. Chemotherapeutic agents such as paclitaxel [1], cisplatin [2], and adriamycin [3] are relevant to tumor apoptosis. Combined with triple therapy, urushiol increases the eradication rate of Helicobacter pylori to 100% [6,20], while synergistic drugs (2% chlorhexidine (CHX), 6% NaOCl, and 0.01% urushiol solution) decrease the growth rate of Streptococcus mutans [8]. As another main constituent of turpentine, levopimaric acid and its derivatives display activity on renal cancer, leukemia, colon cancer, and breast cancer cell lines at a concentration of 10−5 M [21]. We studied their enzymatic bioactivity against HDAC2 (Western blot) and analyzed the probable binding-modes of the most active compound using molecular docking algorithms
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