Novel C15 Triene Triazole, D-A Derivatives Anti-HepG2, and as HDAC2 Inhibitors: A Synergy Study

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.

Anticancer effects of Pimaric acid is mediated via endoplasmic reticulum stress, caspase-dependent apoptosis, cell cycle arrest, and inhibition of cell migration in human ovarian cancer cells

“…The results suggested a tremendous increase in the number of G2/M phase cells compared to the S phase and G0/G1, clearly indicating that Pimaric acid induced G2/M phase cell cycle arrest. Cell cycle arrest has been reported by levopimaric acid in human hepatoma cells (Qi et al, 2018). Western blotting analysis also showed that the expression of Cyclin-B1 diminished after increasing the molecule concentrations.…”

Histone deacetylase‑2: A potential regulator and therapeutic target in liver disease (Review)

“…N-(2-amino-5-substituted phenyl) benzamide significantly induced HCT116 cell death by specifically targeting HDAC2 ( 62 ). In addition, the effects of C15 urushiol and its triazole derivatives on the apoptosis of liver cancer cells have been qualitatively and quantitatively verified ( 132 ). Venturelli et al ( 133 ) reported that 6- and 8-prenylnaringenin enter into the 'foot pocket' of HDAC2 and combine with zinc ion of their catalytic center, subsequently inhibiting excessive proliferation of melanoma cells.…”

Improved Anticancer Activities of a New Pentafluorothio-Substituted Vorinostat-Type Histone Deacetylase Inhibitor

“…Target compound SF5-SAHA was obtained in high yield (87%) from SF5-SAHEt in aqueous hydroxylamine under basic conditions. Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”

“…However, severe drawbacks have emerged during the clinical application of single HDAC inhibitors such as intrinsic or acquired drug resistance. Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”

“…In the present report, a new analog of SAHA with a 4-pentafluorosulfanyl substituted cap phenyl ring is prepared, and its anticancer activities and modes of action are described in comparison with the parent compound SAHA as a reference compound (Figure 1). Hence, the search for new HDAC inhibitors with improved activities has become a relevant and prospering field of anticancer research and several HDAC inhibitors with promising effects on prostate cancer and liver cancer were recently described [4][5][6][7][8].…”