Quantitative Structure-Cytotoxicity Relationship of Azulene Amide Derivatives

Abstract

Background/aim: Very few studies of anticancer activity of azulene amides led us to investigate the cytotoxicity of 21 N-alkylazulene-1-carboxamides introduced either with 3-methyl [1-7], 7-isopropyl-3-methyl [8-14] or 2-methoxy group [15-21] Materials and Methods: Tumor-specificity (TS) was calculated by the ratio of mean 50% cytotoxic concentration (CC₅₀) against three normal human oral mesenchymal cells to that against four human oral squamous cell carcinoma (OSCC) cell lines. Potency-selectivity expression (PSE) was calculated by dividing TS value by CC₅₀ value against OSCC cell lines. Apoptosis-inducing activity was evaluated by caspase-3 activation and appearance of subG₁ cell population.

Results: [8-14] showed higher TS and PSE values, than [1-7] and [15-21] The most active compound [8-14] induced apoptosis in C9-22 OSCC cells at 4-times higher CC₅₀ Quantitative structure-activity relationship analysis of [1-14] demonstrated that their tumor-specificity was correlated with chemical descriptors that explain the molecular shape and hydrophobicity.

Conclusion: 7-Isopropyl-3-methyl-N-propylazulene-1-carboxamide [8] can be a potential candidate of lead compound for manufacturing new anticancer drug.

Keywords: Azulene amides; QSAR; apoptosis tumor specificity; chemical descriptor; hydrophobicity; molecular shape; oral squamous cell carcinoma.