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Article

Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer

1
State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China
2
Center for Tissue Engineering and Stem Cell Research, Key Laboratory of Regenerative Medicine of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang 550004, China
3
School of Pharmacy, Guizhou Medical University, Guian New Districtc, Guiyang 550025, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Stefania-Felicia Barbuceanu and Octavian Tudorel Olaru
Molecules 2022, 27(13), 4040; https://doi.org/10.3390/molecules27134040
Received: 10 May 2022 / Revised: 16 June 2022 / Accepted: 20 June 2022 / Published: 23 June 2022
As a typical dibenzylisoquinoline alkaloid, tetrandrine (TET) is clinically used for the treatment of silicosis, inflammatory pulmonary, and cardiovascular diseases in China. Recent investigations have demonstrated the outstanding anticancer activity of this structure, but its poor aqueous solubility severely restricts its further development. Herein, a series of its 14-N-amino acid-substituted derivatives with improved anticancer effects and aqueous solubility were designed and synthesized. Among them, compound 16 displayed the best antiproliferative activity against human colorectal cancer (HCT-15) cells, with an IC50 value of 0.57 μM. Compared with TET, 16 was markedly improved in terms of aqueous solubility (by 5-fold). Compound 16 significantly suppressed the colony formation, migration, and invasion of HCT-15 cells in a concentration-dependent manner, with it being more potent in this respect than TET. Additionally, compound 16 markedly impaired the morphology and motility of HCT-15 cells and induced the death of colorectal cancer cells in double-staining and flow cytometry assays. Western blot results revealed that 16 could induce the autophagy of HCT-15 cells by significantly decreasing the content of p62/SQSTM1 and enhancing the Beclin-1 level and the ratio of LC3-II to LC3-I. Further study showed that 16 effectively inhibited the proliferation, migration, and tube formation of umbilical vein endothelial cells, manifesting in a potent anti-angiogenesis effect. Overall, these results revealed the potential of 16 as a promising candidate for further preclinical studies. View Full-Text
Keywords: tetrandrine derivatives; amino acid; human colorectal cancer cell; autophagy; anti-angiogenesis tetrandrine derivatives; amino acid; human colorectal cancer cell; autophagy; anti-angiogenesis
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MDPI and ACS Style

Wang, Y.-C.; Zhang, R.-H.; Hu, S.-C.; Zhang, H.; Yang, D.; Zhang, W.-L.; Zhao, Y.-L.; Cui, D.-B.; Li, Y.-J.; Pan, W.-D.; Liao, S.-G.; Zhou, M. Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer. Molecules 2022, 27, 4040. https://doi.org/10.3390/molecules27134040

AMA Style

Wang Y-C, Zhang R-H, Hu S-C, Zhang H, Yang D, Zhang W-L, Zhao Y-L, Cui D-B, Li Y-J, Pan W-D, Liao S-G, Zhou M. Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer. Molecules. 2022; 27(13):4040. https://doi.org/10.3390/molecules27134040

Chicago/Turabian Style

Wang, Yu-Chan, Rong-Hong Zhang, Sheng-Cao Hu, Hong Zhang, Dan Yang, Wen-Li Zhang, Yong-Long Zhao, Dong-Bing Cui, Yong-Jun Li, Wei-Dong Pan, Shang-Gao Liao, and Meng Zhou. 2022. "Design, Synthesis, and Biological Evaluation of N14-Amino Acid-Substituted Tetrandrine Derivatives as Potential Antitumor Agents against Human Colorectal Cancer" Molecules 27, no. 13: 4040. https://doi.org/10.3390/molecules27134040

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