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

• Published in: Anticancer research Vol. 38; no. 8; pp. 4449 - 4457
• Main Authors: Nagai, Junko, Shi, Haixia, Kubota, Yuka, Bandow, Kenjiro, Okudaira, Noriyuki, Uesawa, Yoshihiro, Sakagami, Hiroshi, Tomomura, Mineko, Tomomura, Akito, Takao, Koichi, Sugita, Yoshiaki
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.08.2018
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic drugs; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biological activity; Biotechnology; Cancer; Carcinoma, Squamous Cell - drug therapy; Cell Line; Cell Line, Tumor; Chemical modification; Chemical synthesis; Child; Chromones - chemistry; Chromones - pharmacology; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Female; Humans; Keratinocytes; Materials selection; Mathematical analysis; Melphalan; Mouth Neoplasms - drug therapy; Oral squamous cell carcinoma; Organic chemistry; Polarity; Quantitative Structure-Activity Relationship; Quantum chemistry; Selectivity; Squamous cell carcinoma; Structure-activity relationships; Toxicity; Tumor cell lines; Tumor cells; Tumors; keratinocyte toxicity; Pyrano[4,3-b]chromones; apoptosis induction; tumor selectivity; QSAR analysis; molecular shape; cytotoxicity
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12747

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. 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 (CC ) 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 CC 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. 8-Chloro-4,4a-dihydro-3-methoxy-3-methyl-3H,10H-pyrano[4,3-b][1]benzopyran-10-one ( ) and 3-ethoxy-4,4a-dihydro-8-methoxy-3H,10H-pyrano[4,3-b][1]benzopyran-10-one ( ) had the highest TS, higher than that of 5-flurouracil and melphalan, without induction of apoptosis. Compound 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. Chemical modification of may be a potential choice for designing a new type of anticancer drug.