Tumor-Specificity, Neurotoxicity, and Possible Involvement of the Nuclear Receptor Response Pathway of 4,6,8-Trimethyl Azulene Amide Derivatives

Abstract

Background: Very few papers covering the anticancer activity of azulenes have been reported, as compared with those of antibacterial and anti-inflammatory activity. This led us to investigate the antitumor potential of fifteen 4,6,8-trimethyl azulene amide derivatives against oral malignant cells. Methods: 4,6,8-Trimethyl azulene amide derivatives were newly synthesized. Anticancer activity was evaluated by tumor-specificity against four human oral squamous cell carcinoma (OSCC) cell lines over three normal oral cells. Neurotoxicity was evaluated by cytotoxicity against three neuronal cell lines over normal oral cells. Apoptosis induction was evaluated by Western blot and cell cycle analyses. Results: Among fifteen derivatives, compounds 7, 9, and 15 showed the highest anticancer activity, and relatively lower neurotoxicity than doxorubicin, 5-fluorouracil (5-FU), and melphalan. They induced the accumulation of a comparable amount of a subG1 population, but slightly lower extent of caspase activation, as compared with actinomycin D, used as an apoptosis inducer. The quantitative structure–activity relationship analysis suggests the significant correlation of tumor-specificity with a 3D shape of molecules, and possible involvement of inflammation and hormone receptor response pathways. Conclusions: Compounds 7 and 15 can be potential candidates of a lead compound for developing novel anticancer drugs.

Effects of Guaiazulene on Lipid Peroxidation and Antioxidant Defense System in <i>Drosophila melanogaster</i>

“…In the studies carried out, it has been observed that Gua has radical scavenging properties, can protect cells against oxidative stress, can be used as an antioxidant and antiproliferative agent, and heals cells with hepatotoxicity [42,43]. In addition, it has been reported that Gua has antiretroviral activity against HIV 1 virus and can be used in anticancer drugs in another study [40,44,45]. Park et al (2021), also stated that Gua showed the significant ABTS+ radical scavenging activity similar to ascorbic acid [46].…”

Potentiation of Anticancer Activity of G2/M Blockers by Mild Hyperthermia

“…We have reported that pyoktanin blue (30), 1,5-diaryl-3-oxo-1,4-pentadienes (31), 4,6,8-trimethyl azulene amide derivatives (32), and pyrazole-based hybrids carrying hydrazone and zincbinding benzenesulfonamide pharmacophores (33) showed high tumor selectivity for OSCC, however induced only slight activation of caspase-3 in Ca9-22 cells, suggesting nonapoptotic cell death.…”