Synthesis of 5-Alkynyltetrandrine Derivatives and Evaluation of their Anticancer Activity on A549 Cell Lines

Author(s): Nana Niu, Tingli Qu, Jinfang Xu, Xiaolin Lu, Graham J. Bodwell*, Zhengbao Zhao*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 12 , 2019

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Graphical Abstract:


Abstract:

Background: Lung cancer is one of the most prevalent malignancies and thus the development of novel therapeutic agents for managing lung cancer is imperative. Tetrandrine, a bis-benzyltetrahydroisoquinoline alkaloid isolated from Stephania tetrandra S. Moore, has been found to exert cytotoxic effects on cancerous cells.

Methods: A series of 5-alkynyltetrandrine derivatives was synthesized via the Sonogashira cross-coupling reactions and evaluated as potential anti-tumor agents. The anti-tumor activities of 12 compounds on lung cancer cells (A549) were evaluated using the MTT method. The population of apoptotic cells was measured using a TUNEL assay. Real-time PCR quantified the gene expression levels of Bcl-2, Bax, survivin and caspase-3. The content of Cyt-C was detected using a Human Cyt-C ELISA kit.

Results: Most of these compounds exhibited better activities than tetrandrine itself on A549 cells. Among them, compound 7 showed the highest cytotoxicity among the tested compounds against human lung adenocarcinoma A549 cells with an IC50 of 2.94 µM. Preliminary mechanistic studies indicated that compound 7 induced apoptosis of human lung cancer A549 cells and increased the level of the proapoptotic gene Bax, release of Cyt-C from mitochondria and activation of caspase-3 genes.

Conclusion: The results suggest that compound 7 exerts its antitumor activity against A549 cells through the induction of the intrinsic (mitochondrial) apoptotic pathway. These findings will contribute to the future design of more effective anti-tumor agents in lung cancer therapy.

Keywords: Tetrandrine, Sonogashira coupling, A549 cells, anti-tumor activity, MTT, apoptosis.

[1]
Torre, L.A.; Siegel, R.L.; Jemal, A. Lung cancer statistics. Adv. Exp. Med. Biol., 2016, 893, 1-19.
[2]
Ahmed, F.F.; Abd El-Hafeez, A.A.; Abbas, S.H.; Abdelhamid, D.; Abdel-Aziz, M. New 1,2,4-triazole-Chalcone hybrids induce Caspase-3 dependent apoptosis in A549 human lung adenocarcinoma cells. Eur. J. Med. Chem., 2018, 151, 705-722.
[3]
Wong, R.S. Apoptosis in cancer: From pathogenesis to treatment. J. Exp. Clin. Cancer Res., 2011, 30, 87-100.
[4]
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35, 495-516.
[5]
Huang, Y.T.; Hong, C.Y. Tetrandrine. Cardiovasc. Drug Rev., 1998, 16, 1-15.
[6]
Xu, W.; Debeb, B.G.; Lacerda, L.; Li, J.; Woodward, W.A. Tetrandrine, a compound common in chinese traditional medicine, preferentially kills breast cancer Tumor Initiating Cells (TICs) in vitro. Cancers, 2011, 3, 2274-2285.
[7]
Chen, S.; Liu, W.; Wang, K.; Fan, Y.; Chen, J.; Ma, J.; Wang, X.; He, D.; Zeng, J.; Li, L. Tetrandrine inhibits migration and invasion of human renal cell carcinoma by regulating Akt/NF-κB/MMP-9 signaling. PLoS One, 2017, 12e0173725
[8]
Junhyuk, L.; Gyung, H.K.; Kyung, C.K.; Kyung, M.K.; Dong, I.P.; Byung, T.C.; Ho, S.K.; Yong, T.L.; Yung, H.C. Tetrandrineinduced cell cycle arrest and apoptosis in A549 human lung carcinoma cells. Int. J. Oncol.,, 2002, 21, 1239-1244.
[9]
Xu, M.; Sheng, L.; Zhu, X.; Zeng, S.; Chi, D.; Zhang, G.J. Protective effect of tetrandrine on doxorubicin-induced cardiotoxicity in rats. Tumori, 2010, 96, 460-464.
[10]
Qian, J.Q. Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives. Acta Pharmacol. Sin., 2002, 23, 1086-1092.
[11]
Li, X.; Su, B.; Liu, R.; Wu, D.; He, D. Tetrandrine induces apoptosis and triggers easpase cascade in human bladder cancer cells. J. Surg. Res., 2011, 166, 45-51.
[12]
Hyun, S.C.; Seung, H.C.; Youn, S.C. Synergistic effect of ERK inhibition on tetrandrine-induced apoptosis in A549 human lung carcinoma cells. J. Vet. Sci., 2009, 10, 23-28.
[13]
Wei, N.; Sun, H.; Wang, F.; Liu, G.H. A novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glyeoprotein. Cancer Chemother. Pharmacol., 2011, 67, 1017-1025.
[14]
Lan, J.; Wang, N.; Huang, L.; Liu, Y.; Ma, X.; Lou, H.; Pan, W. Design and synthesis of novel tetrandrine derivatives as potential anti-tumor agents against human hepatocellular carcinoma. Eur. J. Med. Chem., 2017, 127, 554-566.
[15]
Song, J.; Lan, J.; Chen, C.; Hu, S.; Song, J.; Liu, W.; Zeng, X.; Lou, H.; Ben-David, Y.; Pan, W. Design, synthesis and bioactivity investigation of tetrandrine derivatives as potential anti-cancer agents. MedChemComm, 2018, 9, 1131-1141.
[16]
Cui, Y.; Xu, M.; Mao, J.; Ouyang, J.F.; Xu, R.; Yu, Y. Synthesis of berbamine acetyl glycosides and evaluation of antitumor activity. Eur. J. Med. Chem., 2012, 54, 867-872.
[17]
Liu, Y.; Huang, L.; Sun, Q.; Zhang, M.; Li, T.; Liang, G.; Pan, W. Syntheses and anti-cancer activities of derivatives of tetrandrine and fangchinoline. Chem. Res. Chin. Univ., 2014, 30, 937-940.
[18]
Lan, J.; Huang, L.; Lou, H.; Chen, C.; Liu, T.; Hu, S.; Pan, W. Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity. Eur. J. Med. Chem., 2018, 143, 1968-1980.
[19]
Wu, C.Z.; Lai, L.; Hu, X.; Lei, R.R.; Yang, Y.F. Synthesis and antitumor activity of tetrandrine derivatives. J. Asian Nat. Prod. Res., 2013, 15, 993-1002.
[20]
Wei, X.; Qu, T.L.; Yang, Y.F.; Xu, J.F.; Li, X.W.; Zhao, Z.B.; Guo, Y.W. Design and synthesis of new tetrandrine derivatives and their antitumor activities. J. Asian Nat. Prod. Res., 2016, 18, 966-975.
[21]
Jin, T.; Yang, Q.H.; Guo, W.F.; Xu, J.F.; Qu, T.L.; Bodwell, G.J.; Zhao, Z.B. Synthesis of Tetrandrine derivatives and their anti-tumor activities. ChemXpress, 2017, 11, 134.
[22]
Niu, N.N.; Jin, T.; Li, X.; Xu, J.F.; Qu, T.L.; Bodwell, G.J.; Zhao, Z.B. Design and synthesis of tetrandrine derivatives as potential anti-tumor agents against A549 cell lines. ChemistrySelect, 2019, 4, 196-201.
[23]
Wang, P.P.; Wang, L.; Yang, J.S.; Chen, D.L. Preparation and drug composition of bis-benzyl-isoquinoline class alkaloids. U.S. Patent 6,617,335, September 9, 2003.
[24]
Xu, R.Z.; Rong, F.; Xie, F.W.; Ai, H.X. Tetrandrine derivatives with substituted 5-carbon, preparation method and use. W.O. Patent 026383, February 28, 2013.
[25]
Yang, P.; Cheng, J.K.; Wu, L.X. Preparation of 5-pyrine base compound and use in anticancer drug sensitizer. C.N. Patent 102,875,560, January 16, 2012.
[26]
Zhu, L.; Liu, X.; Li, D.; Sun, S.; Wang, Y.; Sun, X. Autophagy is a pro-survival mechanism in ovarian cancer against the apoptotic effects of euxanthone. Biomed. Pharmacother., 2018, 103, 708-718.
[27]
Mohamed, M.S.; Abdelhamid, A.O.; Almutairi, F.M.; Ali, A.G.; Bishr, M.K. Induction of apoptosis by pyrazolo[3,4-d]pyridazine derivative in lung cancer cells via disruption of Bcl-2/Bax expression balance. Bioorg. Med. Chem., 2018, 26, 623-629.
[28]
Fan, X.; Wang, P.; Sun, Y.; Jiang, J.; Du, H.; Wang, Z.; Li, H. Induction of apoptosis by an oleanolic acid derivative in SMMC-7721 human hepatocellular carcinoma cells is associated with mitochondrial dysfunction. Oncol. Lett., 2018, 15, 2821-2828.
[29]
Manickam, P.; Kaushik, A.; Karunakaran, C.; Bhansali, S. Recent advances in cytochrome c biosensing technologies. Biosens. Bioelectron., 2017, 87, 654-668.


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Article Details

VOLUME: 19
ISSUE: 12
Year: 2019
Published on: 02 December, 2019
Page: [1454 - 1462]
Pages: 9
DOI: 10.2174/1871520619666190408132249
Price: $65

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