Quantitative Structure-cytotoxicity Relationship of 3-Benzylidenechromanones

Aim: Sixteen 3-benzylidenechromanones were subjected to quantitative structure–activity relationship (QSAR) analysis based on their cytotoxicity and tumor-specificity, in order to examine their new biological activities. Materials and Methods: Cytotoxicity against two human oral squamous cell carcinoma cell lines, two mesenchymal and two epithelial normal oral cells, was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tumor-specificity (TS) was evaluated by the ratio of the mean CC50 (50% cytotoxic concentration) against normal cells to that against tumor cell lines. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. Results: 3-Benzylidenechromanone derivatives that have a methoxy group at 7-position of the chromanone ring and hydroxyl or methoxy group at 4’-position of benzene ring showed relatively higher TS values, exceeding those of doxorubicin (DXR) and 5-fluorouracil (5-FU). Since these anticancer drugs were highly cytotoxic to normal keratinocytes, QSAR analysis was performed with oral carcinoma and mesenchymal normal cells. Tumor-specificity was well correlated with 3D-MoRSE descriptors (that relate to three dimensional shapes) and Edge adjacency indices (that relate to two dimensional shapes and polarization). Introduction of hydroxyl group at 3’-position of benzene ring significantly elevated the tumor-specificity. Conclusion: Molecular shape, size and polarization are useful markers for the evaluation of tumor-specificity of 3-benzylidenechromanone derivatives.