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

Junko Nagai; Haixia Shi; Yuka Kubota; Kenjiro Bandow; Noriyuki Okudaira; Yoshihiro Uesawa; Hiroshi Sakagami; Mineko Tomomura; Akito Tomomura; Koichi Takao; Yoshiaki Sugita

doi:10.21873/anticanres.12747

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

Anticancer Res. 2018 Aug;38(8):4449-4457. doi: 10.21873/anticanres.12747.

Authors

Junko Nagai¹, Haixia Shi^{2

3}, Yuka Kubota⁴, Kenjiro Bandow⁵, Noriyuki Okudaira⁶, Yoshihiro Uesawa⁷, Hiroshi Sakagami², Mineko Tomomura⁵, Akito Tomomura⁵, Koichi Takao⁴, Yoshiaki Sugita⁴

Affiliations

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.

PMID: 30061209
DOI: 10.21873/anticanres.12747

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.

Keywords: Pyrano[4,3-b]chromones; QSAR analysis; apoptosis induction; cytotoxicity; keratinocyte toxicity; molecular shape; tumor selectivity.

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carcinoma, Squamous Cell / drug therapy
Cell Line
Cell Line, Tumor
Child
Chromones / chemistry*
Chromones / pharmacology*
Doxorubicin / pharmacology
Female
Humans
Mouth Neoplasms / drug therapy
Quantitative Structure-Activity Relationship

Substances

Antineoplastic Agents
Chromones
Doxorubicin