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.