Noriyuki Okudaira

Quantitative Structure–Cytotoxicity Relationship of 3-(N-Cyclicamino)chromone Derivatives

Background/Aim: 4H-1-Benzopyran-4-ones (chromones) provide a backbone structure for the chemical synthesis of potent anticancer drugs. In contrast to 2-(N-cyclicamino)chromones, the biological activity of 3-(N-cyclicamino)chromones has not been reported. In this study, cytotoxicity of 15 3-(N-cyclicamino)chromone derivatives was investigated and subjected to quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-specificity (TS) was evaluated as the ratio of mean 50% cytotoxic concentration (CC50) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by the CC50 against tumor cells. Apoptosis induction was evaluated by morphological observation, western blot analysis and cell-cycle analysis. For QSAR analysis, a total of 3,096 physicochemical, structural and quantum chemical features were calculated from the most stabilized structure optimized using CORINA. Results: 3-(4-phenyl-1-piperazinyl)-4H-1-benzopyran-4-one (3a) had the highest tumor specificity, comparable with that of melphalan, without induction of apoptosis. Compound 3a caused cytostatic growth inhibition and had much lower cytotoxicity against human oral keratinocytes compared to doxorubicin. TS of the 15 3-(N-cyclicamino)chromones was correlated with 3D structure and lipophilicity. Conclusion: Chemical modification of 3a may be a potential choice for designing a new type of anticancer drug.

Quantitative Structure–Cytotoxicity Relationship of 2-(N-cyclicamino)chromone Derivatives

Background/Aim: 4H-1-Benzopyran-4-ones (chromones) have provided backbone structure for the chemical synthesis of potent anticancer drugs. In this study, the cytotoxicity of fifteen 2-(N-cyclicamino)chromone derivatives was investigated and subjected to quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by ratio of mean 50% cytotoxic concentration (CC50) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC50 against tumor cells. Apoptosis induction was evaluated by morphological observation, western blot analysis and cell-cycle analysis. For QSAR analysis, a total of 3,089 physicochemicals, structural and quantum chemical features were calculated from the most stabilized structure optimized using Corina. Results: 7-Methoxy-2-(4-morpholinyl)-4H-1-benzopyran-4-one (5c) showed highest tumor-specificity, comparable with that of doxorubicin, without inducing apoptosis. Tumor-specificity of fifteen 2-(N-cyclicamino) chromones was correlated with molecular shape, especially 3D-structure. Conclusion: Chemical modification of 5c may be a potential choice for designing a new type of anticancer drugs.

Quantitative Structure–Cytotoxicity Relationship of Pyrano[4,3-b]chromones

Background/Aim: 4H-1-Benzopyran-4-one (chromone) provides a backbone structure for the chemical synthesis of potent anticancer drugs. Since studies of the biological activity of pyrano[4,3-b]chromones are limited, we investigated a total of 20 pyrano[4,3-b]chromones (10 sets of diastereomers) for their cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and human normal oral cells, and then carried out a quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Tumor-specificity (TS) was evaluated by the ratio of mean 50% cytotoxic concentration (CC50) against normal oral cells to that against human OSCC cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by the CC50 against tumor cells. Apoptosis induction was evaluated by morphological observation, western blot analysis and cell-cycle analysis. For QSAR analysis, a total of 3,072 physicochemical, structural and quantum chemical features were calculated from the most stabilized structure optimized using CORINA. Results: 8-Chloro-4,4a-dihydro-3-methoxy-3-methyl-3H,10H-pyrano[4,3-b][1]benzopyran-10-one (16) and 3-ethoxy-4,4a-dihydro-8-methoxy-3H,10H-pyrano[4,3-b][1]benzopyran-10-one (17) had the highest TS, higher than that of 5-flurouracil and melphalan, without induction of apoptosis. Compound 16 induced cytostatic growth inhibition and much lower cytotoxicity against human normal oral keratinocytes compared to doxorubicin. TS of 20 pyrano[4,3-b]chromones was correlated with 3D structure, polarity, ionic potential and electric state. Conclusion: Chemical modification of 16 may be a potential choice for designing a new type of anticancer drug.

Cytotoxicity, apoptosis, and QSAR studies of phenothiazine derived methoxylated chalcones as anticancer drug candidates

In the present study, chalcones “(E)-1-(10H-phenothiazine-2-yl)-3-aryl-prop-2-en-1-ones, FS1-11” were successfully synthesized via base-catalyzed Claisen–Schmidt condensation. Chemical structures of the compounds were confirmed by 1H NMR, 13C NMR, and HRMS techniques. Aryl part of the chalcone was changed as mono, di, and trimethoxylated phenyls. Cytotoxicities of the phenothiazine derivatives were evaluated against four human oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and HSC-4) and three human normal oral cells (HGF, HPLF, and HPC) by MTT test. The CC50 values of the compounds were calculated in the range of 0.9–109.8 µM towards OSCC malign cell lines. Trimethoxylated compound FS6, (E)-1-(10H-phenothiazine-2-yl)-3-(2,4,5-trimethoxyphenyl)-prop-2-en-1-one, was found the most selective cytotoxic compound among the series with the highest selectivity index (SI) (SI = 76.5) and potency-selectivity expression (PSE) (PSE = >1285; > 1602) values. Western blot analysis demonstrated that FS6 (8–64 μM) induced the production of cleaved product of PARP and the activation of caspase-3 in HSC-2 cells, suggesting the induction of apoptosis by FS6. QSAR analysis suggested that the tumor specificity of the chalcones correlated with their molecular shape, volume, and electrostatic properties.