Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents

Lin, Hong-Jhih; Ho, Jinn-Hsuan; Tsai, Li-Chen; Yang, Fang-Yu; Yang, Ling-Ling; Kuo, Cheng-Deng; Chen, Lih-Geeng; Liu, Yi-Wen; Wu, Jin-Yi

doi:10.3390/molecules25030677

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Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents

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Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi 60004, Taiwan

Department of Chemical Engineering, College of Engineering, National Taiwan University of Science and Technology, Taipei 10607, Taiwan

Department of Pharmacognosy, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan

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Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua 50006, Taiwan

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Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan

Author to whom correspondence should be addressed.

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These authors made equal contribution to this work.

Molecules 2020, 25(3), 677; https://doi.org/10.3390/molecules25030677

Received: 8 January 2020 / Revised: 29 January 2020 / Accepted: 2 February 2020 / Published: 5 February 2020

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Abstract

The objective of this study was to synthesize the 9-/13-position substituted berberine derivatives and evaluate their cytotoxic and photocytotoxic effects against three human cancer cell lines. Among all the synthesized compounds, 9-O-dodecyl- (5e), 13-dodecyl- (6e), and 13-O-dodecyl-berberine (7e) exhibited stronger growth inhibition against three human cancer cell lines, (HepG2, HT-29 and BFTC905), in comparison with structurally related berberine (1). These three compounds also showed the photocytotoxicity in human cancer cells in a concentration-dependent and light dose-dependent manner. Through flow cytometry analysis, we found out a lipophilic group at the 9-/13-position of berberine may have facilitated its penetration into test cells and hence enhanced its photocytotoxicity on the human liver cancer cell HepG2. Further, in cell cycle analysis, 5e, 6e, and 7e induced HepG2 cells to arrest at the S phase and caused apoptosis upon irradiation. In addition, photodynamic treatment of berberine derivatives 5e, 6e, and 7e again showed a significant photocytotoxic effects on HepG2 cells, induced remarkable cell apoptosis, greatly increased intracellular ROS level, and the loss of mitochondrial membrane potential. These results over and again confirmed that berberine derivatives 5e, 6e, and 7e greatly enhanced photocytotoxicity. Taken together, the test data led us to conclude that berberine derivatives with a dodecyl group at the 9-/13-position could be great candidates for the anti-liver cancer medicines developments. View Full-Text

Keywords: berberine; lipophilic substituent; anti-cancer activity; photocytotoxicity; reactive oxygen species

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Lin, H.-J.; Ho, J.-H.; Tsai, L.-C.; Yang, F.-Y.; Yang, L.-L.; Kuo, C.-D.; Chen, L.-G.; Liu, Y.-W.; Wu, J.-Y. Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents. Molecules 2020, 25, 677. https://doi.org/10.3390/molecules25030677

AMA Style

Lin H-J, Ho J-H, Tsai L-C, Yang F-Y, Yang L-L, Kuo C-D, Chen L-G, Liu Y-W, Wu J-Y. Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents. Molecules. 2020; 25(3):677. https://doi.org/10.3390/molecules25030677

Chicago/Turabian Style

Lin, Hong-Jhih, Jinn-Hsuan Ho, Li-Chen Tsai, Fang-Yu Yang, Ling-Ling Yang, Cheng-Deng Kuo, Lih-Geeng Chen, Yi-Wen Liu, and Jin-Yi Wu. 2020. "Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents" Molecules 25, no. 3: 677. https://doi.org/10.3390/molecules25030677

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Synthesis and In Vitro Photocytotoxicity of 9-/13-Lipophilic Substituted Berberine Derivatives as Potential Anticancer Agents

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