Abstract
A series of new thiomatrine derivatives was designed and synthesized for their potential application as anticancer agents. The structure of these compounds was characterized by 1H-NMR, 13C-NMR, and ESI-MS spectral analyses. Single crystals of compound 3k were obtained by recrystallization and the structure was further confirmed by X-ray diffraction determination. All the target compounds were evaluated for their in vitro cytotoxicity against human cancer cell lines A549 and HepG2. Among these compounds, the derivative 3aa displayed the most significant anticancer activity against four cancer cell lines with IC50 values in range of 7.8–11.4 μM, indicating much better activity than the parent compound (matrine). The cell cycle analysis revealed that compound 3aa could cause cell cycle arrest of SMMC-7721 and CNE2 cells at G2/M phase. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3aa could significantly induce the apoptosis of SMMC-7721 and CNE2 cells in a dose-dependent manner. Western blot analysis revealed that compound 3aa could induce apoptosis by activating caspase-3, increasing expression of cleaved caspase-3 and reducing the ratio of Bcl-2/Bax.
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References
Browne LJ, Gude C, Rodriguez H, Steele RE, Bhatnager A (1991) ChemInform abstract: fadrozole hydrochloride: a potent, selective, nonsteroidal inhibitor of aromatase for the treatment of estrogen-dependent disease. J Med Chem 34:725–736
Greene TW (2007) Greene’s protective groups in organic synthesis. Wiley Intersci 21:1–15
Kim SM, Park JH, Kim KD, Nam D, Shim BS, Kim SH, Ahn KS, Choi SH, Ahn KS (2014) Brassinin induces apoptosis in PC-3 human prostate cancer cells through the suppression of PI3K/Akt/mTOR/S6K1 signaling cascades. Phytother Res 28:423–431
Koduri ND, Scott H, Hileman B, Cox JD, Coffin M, Glicksberg L, Hussaini SR (2012) Ruthenium catalyzed synthesis of enaminones. Org Lett 14:440–443
Li H, Li X, Bai M, Suo Y, Zhang G, Cao X (2015) Matrine inhibited proliferation and increased apoptosis in human breast cancer MCF-7 cells via upregulation of Bax and downregulation of Bcl-2. Int J Exp Pathol 8:14793–14799
Li H, Tan G, Jiang X, Qiao H, Pan S, Jiang H, Kanwar JR, Sun X (2010) Therapeutic effects of matrine on primary and metastatic breast cancer. Am J Chin Med 38:1115–1130
Li Y, Min G, Xue Q, Chen L, Liu W, Chen H (2004) High-performance liquid chromatographic method for simultaneous determination of sophoridine and matrine in rat plasma. Biomed Chromatogr 18:619–624
Li Z, Luo M, Cai B, Wu L, Huang M, Ur-Rashid H, Jiang J, Wang L (2018) Design, synthesis and biological evaluation of matrine derivatives as potential anticancer agents. Bioorg Med Chem Lett 28:677–683
Liu J, Xue M, Huang X, Wang S, Jiang Z, Zhang L (2012) Pharmacokinetic of four alkaloids of Yanshu injection in Beagel dogs. China J Chin Mater Med 37:1845–1849
Liu TY, Yan S, Hua C, Pan SH, Sun XY (2010) Matrine inhibits proliferation and induces apoptosis of pancreatic cancer cells in vitro and in vivo. Biol Pharm Bull 33:1740–1745
Peng-Yi HU, Qin Z, Hui C, Zhen-Feng WU, Yue PF, Ming Y (2012) Pharmacokinetics and distribution of sophoridine nanoliposomes in rats. Chin J New Drug 21:2662–2666
Qi L, Zhang J, Zhang Z (2013) Determination of four alkaloids in compound Kushen Injection by high performance liquid chromatography with ionic liquid as mobile phase additive. Chin J Chromatogr 31:249–253
Skrott Z, Mistrik M, Andersen KK, Friis S, Majera D, Gursky J, Ozdian T, Bartkova J, Turi Z, Moudry P (2017) Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Natute 552:194–199
Sun M, Cao H, Sun L, Dong S, Bian Y, Han J, Zhang L, Ren S, Hu Y, Liu C (2012) Antitumor activities of kushen: literature review. Evid Based Complement Altern Med 2012:373219–373230
Sun Q, Ma W, Gao Y, Zheng W, Zhang B, Peng Y (2011) Meta-analysis: therapeutic effect of transcatheter arterial chemoembolization combined with compound kushen injection in hepatocellular carcinoma. Afr J Tradit Complem 9:178–188
Tian J, Wang WH, Gao HM, Wang ZM (2007) Determination of matrine, sophoridine and oxymatrine in Compound Kushen Injection by HPLC. Zhongguo Zhong Yao Za Zhi 32:222–224
Wang C-Y, Bai X-Y, Wang C-H (2014) Traditional chinese medicine: a treasured natural resource of anticancer drug research and development. Am J Chin Med 42:543–559
Wang HQ, Jin JJ, Wang J (2015) Matrine induces mitochondrial apoptosis in cisplatin-resistant non-small cell lung cancer cells via suppression of β-catenin/survivin signaling. Oncol Rep 33:2561–2566
Wang L, You Y, Wang S, Liu X, Liu B, Wang J, Lin X, Chen M, Liang G, Yang H (2012) Synthesis, characterization and in vitro anti-tumor activities of matrine derivatives. Bioorg Med Chem Lett 22:4100–4102
Wei R, Yang DY, Jiang WZ, Dai YY, Wan LY, Yang Z (2011) Efficacy of Yanshu injection (a compound Chinese traditional medicine) combined with concurrent radiochemotherapy in patients with stage III nasopharyngeal carcinoma. Zhonghua Zhong Liu Za Zhi 33:391–394
Wu L, Wang G, Wei J, Huang N, Zhang S, Yang F, Li M, Zhou G, Wang L (2011) Matrine derivative YF-18 inhibits lung cancer cell proliferation and migration through down-regulating Skp2. Oncotarget 8:11729–11738
Wu LC, Wen ZS, Qiu YT, Chen XQ, Chen HB, Wei MM, Liu Z, Jiang S, Zhou GB (2013) Largazole arrests cell cycle at G1 phase and triggers proteasomal degradation of E2F1 in lung cancer cells. ACS Med Chem Lett 4:921–926
Xie M, Yi X, Wang R, Wang L, He G, Zhu M, Qi C, Liu Y, Ye Y, Tan S (2014) 14-Thienyl methylene matrine (YYJ18), the derivative from matrine, induces apoptosis of human nasopharyngeal carcinoma cells by targeting MAPK and PI3K/Akt pathways in vitro. Cell Physiol Biochem 33:1475–1483
Ye G, Zhu HY, Li ZX, Ma CH, Fan MS, Sun ZL, Huang CG (2007) LC-MS characterization of efficacy substances in serum of experimental animals treated with Sophora flavescens extracts. Biomed Chromatogr 21:655–660
Yong J, Wu X, Lu C (2015) Anticancer advances of matrine and its derivatives. Curr Pharm Des 21:3673–3680
Zhong LY, Wu H (2006) Current researching situation of mucosal irritant compontents in Araceae family plants. Zhongguo Zhong Yao Za Zhi 31:1561–1563
Zhou W, Xu X, Gao J, Sun P, Li L, Shi X, Li J (2015) TCM matrine inducescell arrest and apoptosis with recovery expression of the hepato-specific miR122a in human hepatocellular carcinoma HepG2 cell line. Int J Clin Exp Med 8:9004–9012
Acknowledgements
This work was supported by the National Natural Science Foundation of China (21402032, 21262005), the high level innovation team and outstanding scholar project of Guangxi institutions of higher education (guijiaoren [2014] 49 hao), Guangxi Natural Science Foundation (2014GXNSFBA118031, 2017GXNSFBA198240) and the State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Guangxi Normal University (CMEMR2017-B14). We also thank Professor Cai Bin of Suzhou Galaxy biopharma, CO., LTD. for the experiment support.
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These authors contributed equally: Zheng Li and Lichuan Wu
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Li, Z., Wu, L., Cai, B. et al. Design, synthesis, and biological evaluation of thiomatrine derivatives as potential anticancer agents. Med Chem Res 27, 1941–1955 (2018). https://doi.org/10.1007/s00044-018-2205-x
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DOI: https://doi.org/10.1007/s00044-018-2205-x