Junko Nagai1, Haixia Shi2,3, Yuka Kubota4, Kenjiro Bandow5, Noriyuki Okudaira6, Yoshihiro Uesawa7, Hiroshi Sakagami2, Mineko Tomomura5, Akito Tomomura5, Koichi Takao4, Yoshiaki Sugita4. 1. Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo, Japan. 2. Department of Traditional Chinese Medicine, Shanghai Ninth People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China. 3. Meikai University Research Institute of Odontology (M-RIO), Saitama, Japan. 4. Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, Japan. 5. Division of Biochemistry, Meikai University School of Dentistry, Saitama, Japan. 6. Division of Pharmacology, Meikai University School of Dentistry, Saitama, Japan. 7. Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo, Japan uesawa@my-pharm.ac.jp.
Abstract
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. Copyright
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. Copyright