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Anticancer Res. 2018 Aug;38(8):4459-4467. doi: 10.21873/anticanres.12748.

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

Author information

1
Department of Traditional Chinese Medicine, Shanghai Ninth People's Hospital, Shanghai Jiatong University School of Medicine, Shanghai, P.R. China haixia.0101@163.com sakagami@dent.meikai.ac.jp.
2
Meikai University Research Institute of Odontology (M-RIO), Saitama, Japan.
3
Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo, 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
Meikai University Research Institute of Odontology (M-RIO), Saitama, Japan haixia.0101@163.com sakagami@dent.meikai.ac.jp.

Abstract

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.

KEYWORDS:

3-(N-Cyclicamino)chromones; QSAR analysis; apoptosis induction; cytotoxicity; molecular shape; tumor selectivity

PMID:
30061210
DOI:
10.21873/anticanres.12748
[Indexed for MEDLINE]

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