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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

The Design, Synthesis, and Evaluation of Evodiamine Derivatives with Hydroxy Groups

Author(s): Zheng Yang, Hui Guo*, Keyao Zhang, Zebo Jiang, Ruyi Jin, Dongyan Guo, Zhi Li, Yuwei Wang* and Lingjie Meng*

Volume 20, Issue 8, 2023

Published on: 13 October, 2022

Page: [1135 - 1146] Pages: 12

DOI: 10.2174/1570180819666220903150621

Price: $65

Abstract

Background: Most of the structural modifications to evodiamine (EVO) have focused on the 3- and 10-positions, while structural modifications to the EVO 2-position have not yet been reported. In this study, we investigated the scaffold diversity and bioactivity of EVO from position 2 to gain more insight into the influence of the chemical space around EVO on bioactivity.

Objective: The study aims to synthesize two derivatives of EVO with hydroxy groups, 8a and 8b, and to investigate the antitumor activity of EVO derivatives with hydroxy groups compared to EVO.

Methods: The synthesized compounds were structurally characterized by 1H NMR, 13C NMR, and mass spectrometry. The effects of compounds 8a, 8b, and EVO on the proliferation of H460, A549, and Eca109 cells in vitro were determined by MTT. The effect of EVO, 8a and 8b on apoptosis of H460 cells was investigated by the annexed V-FITC/propidium iodide (PI) combination assay. The expression of EVO, 8a and 8b on apoptosis-related proteins was examined by Western blot analysis. To simulate the binding ability between small molecules and proteins, molecular docking calculations of EGFRWT and EGFRT790M with 8a and 8b, respectively, were performed using Schrödinger software.

Results: In the cytotoxicity assay, compound 8b showed lower IC50 values for the three tumor cell lines (6.69 μM for H460 cells, 20.02 μM for A549 cells, and 16.47 μM for Eca109 cells) compared to compound 8a and EVO, and 8b induced apoptosis by affecting apoptosis-related proteins CRAF, AKT, and ERK in a late apoptotic manner. The molecular docking results showed that 8b has a good binding ability to EGFR upstream of apoptosis-related proteins.

Conclusion: These findings suggest that 8b has significantly higher antitumor biological activity than EVO and 8a. This antitumor effect has important implications for the study of EVO derivatives in antitumor models.

Keywords: Synthesis, antitumor activity, evodiamine derivatives, MTT, apoptosis, western blot.

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[1]
Petrovska, B. Historical review of medicinal plants′ usage. Pharmacogn. Rev., 2012, 6(11), 1-5.
[http://dx.doi.org/10.4103/0973-7847.95849] [PMID: 22654398]
[2]
Wall, M.E.; Wani, M.C. Camptothecin and taxol: From discovery to clinic. J. Ethnopharmacol., 1996, 51(1-3), 239-254.
[http://dx.doi.org/10.1016/0378-8741(95)01367-9] [PMID: 9213622]
[3]
Buyel, J.F. Plants as sources of natural and recombinant anti-cancer agents. Biotechnol. Adv., 2018, 36(2), 506-520.
[http://dx.doi.org/10.1016/j.biotechadv.2018.02.002] [PMID: 29408560]
[4]
Varghese, R.; Dalvi, Y.B. Natural products as anticancer agents. Curr. Drug Targets, 2021, 22(11), 1272-1287.
[http://dx.doi.org/10.2174/1389450121999201230204526] [PMID: 33390130]
[5]
Kuo, M.L.; Huang, T.S.; Lin, J.K. Curcumin, an antioxidant and anti-tumor promoter, induces apoptosis in human leukemia cells. Biochim. Biophys. Acta Mol. Basis Dis., 1996, 1317(2), 95-100.
[http://dx.doi.org/10.1016/S0925-4439(96)00032-4] [PMID: 8950193]
[6]
Ijaz, S.; Akhtar, N.; Khan, M.S.; Hameed, A.; Irfan, M.; Arshad, M.A.; Ali, S.; Asrar, M. Plant derived anticancer agents: A green approach towards skin cancers. Biomed. Pharmacother., 2018, 103, 1643-1651.
[http://dx.doi.org/10.1016/j.biopha.2018.04.113] [PMID: 29864953]
[7]
Martino, E.; Della Volpe, S.; Terribile, E.; Benetti, E.; Sakaj, M.; Centamore, A.; Sala, A.; Collina, S. The long story of camptothecin: From traditional medicine to drugs. Bioorg. Med. Chem. Lett., 2017, 27(4), 701-707.
[http://dx.doi.org/10.1016/j.bmcl.2016.12.085] [PMID: 28073672]
[8]
Hofmann, E.; Webster, J.; Do, T.; Kline, R.; Snider, L.; Hauser, Q.; Higginbottom, G.; Campbell, A.; Ma, L.; Paula, S. Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers. Bioorg. Med. Chem., 2016, 24(4), 578-587.
[http://dx.doi.org/10.1016/j.bmc.2015.12.024] [PMID: 26762836]
[9]
Zhang, R.; Li, Y.; Cai, Q.; Liu, T.; Sun, H.; Chambless, B. Preclinical pharmacology of the natural product anticancer agent 10-hydroxycamptothecin, an inhibitor of topoisomerase I. Cancer Chemother. Pharmacol., 1998, 41(4), 257-267.
[http://dx.doi.org/10.1007/s002800050738] [PMID: 9488594]
[10]
Bissantz, C.; Kuhn, B.; Stahl, M. A medicinal chemist’s guide to molecular interactions. J. Med. Chem., 2010, 53(14), 5061-5084.
[http://dx.doi.org/10.1021/jm100112j] [PMID: 20345171]
[11]
Barratt, E.; Bronowska, A.; Vondrášek, J.; Černý, J.; Bingham, R.; Phillips, S.; Homans, S.W. Thermodynamic penalty arising from burial of a ligand polar group within a hydrophobic pocket of a protein receptor. J. Mol. Biol., 2006, 362(5), 994-1003.
[http://dx.doi.org/10.1016/j.jmb.2006.07.067] [PMID: 16935302]
[12]
Cramer, J.; Sager, C.P.; Ernst, B. Hydroxyl groups in synthetic and natural-product-derived therapeutics: A perspective on a common functional group. J. Med. Chem., 2019, 62(20), 8915-8930.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00179] [PMID: 31083946]
[13]
Yu, H.; Jin, H.; Gong, W.; Wang, Z.; Liang, H. Pharmacological actions of multi-target-directed evodiamine. Molecules, 2013, 18(2), 1826-1843.
[http://dx.doi.org/10.3390/molecules18021826] [PMID: 23434865]
[14]
Tian, K.; Li, J.; Xu, S. Rutaecarpine: A promising cardiovascular protective alkaloid from Evodia rutaecarpa (Wu Zhu Yu). Pharmacol. Res., 2019, 141, 541-550.
[http://dx.doi.org/10.1016/j.phrs.2018.12.019] [PMID: 30616017]
[15]
Hu, X.; Li, D.; Chu, C.; Li, X.; Wang, X.; Jia, Y.; Hua, H.; Xu, F. Antiproliferative effects of alkaloid evodiamine and its derivatives. Int. J. Mol. Sci., 2018, 19(11), 3403.
[http://dx.doi.org/10.3390/ijms19113403] [PMID: 30380774]
[16]
Guo, Q.; Liu, Y.; Zhao, J.; Wang, J.; Li, Y.; Pang, Y.; Chen, J.; Wang, J. Evodiamine inactivates NF-κB and potentiates the antitumor effects of gemcitabine on tongue cancer both in vitro and in vivo. OncoTargets Ther., 2018, 12, 257-267.
[http://dx.doi.org/10.2147/OTT.S181062] [PMID: 30643424]
[17]
Huang, G.; Roos, D.; Stadtmüller, P.; Decker, M. A simple heterocyclic fusion reaction and its application for expeditious syntheses of rutaecarpine and its analogs. Tetrahedron Lett., 2014, 55(26), 3607-3609.
[http://dx.doi.org/10.1016/j.tetlet.2014.04.120]
[18]
Guo, X.X.; Li, X.P.; Zhou, P.; Li, D.Y.; Lyu, X.T.; Chen, Y.; Lyu, Y.W.; Tian, K.; Yuan, D.Z.; Ran, J.H.; Chen, D.L.; Jiang, R.; Li, J. Evodiamine induces apoptosis in SMMC-7721 and HepG2 cells by suppressing NOD1 signal pathway. Int. J. Mol. Sci., 2018, 19(11), 3419.
[http://dx.doi.org/10.3390/ijms19113419] [PMID: 30384473]
[19]
Wu, W.S.; Chien, C.C.; Liu, K.H.; Chen, Y.C.; Chiu, W.T. Evodiamine prevents glioma growth, induces glioblastoma cell apoptosis and cell cycle arrest through JNK activation. Am. J. Chin. Med., 2017, 45(4), 879-899.
[http://dx.doi.org/10.1142/S0192415X17500471] [PMID: 28514905]
[20]
Wu, J.; Wang, J.; Zhao, H. Commentary regarding “Solubilities of evodiamine in twelve organic solvents from T = (283.2 to 323.2) K”. J. Chem. Thermodyn., 2019, 129, 145-147.
[http://dx.doi.org/10.1016/j.jct.2018.09.015]
[21]
Fan, J.P.; Yang, X.M.; Xu, X.K.; Xie, Y.L.; Zhang, X.H. Solubility of rutaecarpine and evodiamine in (ethanol+water) mixed solvents at temperatures from (288.2 to 328.2). K. J. Chem. Thermodyn., 2015, 83, 85-89.
[http://dx.doi.org/10.1016/j.jct.2014.12.004]
[22]
Wang, S.; Fang, K.; Dong, G.; Chen, S.; Liu, N.; Miao, Z.; Yao, J.; Li, J.; Zhang, W.; Sheng, C. Scaffold diversity inspired by the natural product evodiamine: Discovery of highly potent and multitargeting antitumor agents. J. Med. Chem., 2015, 58(16), 6678-6696.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00910] [PMID: 26226379]
[23]
Fang, K.; Dong, G.Q.; Gong, H.; Liu, N.; Li, Z.G.; Zhu, S.P.; Miao, Z.Y.; Yao, J.Z.; Zhang, W.N.; Sheng, C.Q. Design, synthesis and biological evaluation of E-ring modified evodiamine derivatives as novel antitumor agents. Chin. Chem. Lett., 2014, 25(7), 978-982.
[http://dx.doi.org/10.1016/j.cclet.2014.03.043]
[24]
Dong, G.; Wang, S.; Miao, Z.; Yao, J.; Zhang, Y.; Guo, Z.; Zhang, W.; Sheng, C. New tricks for an old natural product: Discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations. J. Med. Chem., 2012, 55(17), 7593-7613.
[http://dx.doi.org/10.1021/jm300605m] [PMID: 22867019]
[25]
Dong, G.; Sheng, C.; Wang, S.; Miao, Z.; Yao, J.; Zhang, W. Selection of evodiamine as a novel topoisomerase I inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents. J. Med. Chem., 2010, 53(21), 7521-7531.
[http://dx.doi.org/10.1021/jm100387d] [PMID: 20942490]
[26]
Deng, J.D.; Lei, S.; Jiang, Y.; Zhang, H.H.; Hu, X.L.; Wen, H.X.; Tan, W.; Wang, Z. A concise synthesis and biological study of evodiamine and its analogues. Chem. Commun. (Camb.), 2019, 55(21), 3089-3092.
[http://dx.doi.org/10.1039/C9CC00434C] [PMID: 30785464]
[27]
Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene, 2006, 366(1), 2-16.
[http://dx.doi.org/10.1016/j.gene.2005.10.018] [PMID: 16377102]
[28]
Guo, G.; Gong, K.; Wohlfeld, B.; Hatanpaa, K.J.; Zhao, D.; Habib, A.A. Ligand-independent EGFR signaling. Cancer Res., 2015, 75(17), 3436-3441.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-0989] [PMID: 26282175]
[29]
Park, H.R.; Kim, T.M.; Lee, Y.; Kim, S.; Park, S.; Ju, Y.S.; Kim, M.; Keam, B.; Jeon, Y.K.; Kim, D.W.; Heo, D.S. Acquired resistance to third-generation EGFR tyrosine kinase inhibitors in patients with de novo EGFRT790M-Mutant NSCLC. J. Thorac. Oncol., 2021, 16(11), 1859-1871.
[http://dx.doi.org/10.1016/j.jtho.2021.06.013] [PMID: 34242789]
[30]
Takata, S.; Takigawa, N.; Segawa, Y.; Kubo, T.; Ohashi, K.; Kozuki, T.; Teramoto, N.; Yamashita, M.; Toyooka, S.; Tanimoto, M.; Kiura, K. STAT3 expression in activating EGFR-driven adenocarcinoma of the lung. Lung Cancer, 2012, 75(1), 24-29.
[http://dx.doi.org/10.1016/j.lungcan.2011.05.015] [PMID: 21684622]
[31]
Jorissen, R.; Walker, F.; Pouliot, N.; Garrett, T.P.; Ward, C.W.; Burgess, A.W. Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp. Cell Res., 2003, 284(1), 31-53.
[http://dx.doi.org/10.1016/S0014-4827(02)00098-8] [PMID: 12648464]
[32]
Zhang, J.; Kalyankrishna, S.; Wislez, M.; Thilaganathan, N.; Saigal, B.; Wei, W.; Ma, L.; Wistuba, I.I.; Johnson, F.M.; Kurie, J.M. SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am. J. Pathol., 2007, 170(1), 366-376.
[http://dx.doi.org/10.2353/ajpath.2007.060706] [PMID: 17200208]
[33]
Marcotte, R.; Zhou, L.; Kim, H.; Roskelly, C.D.; Muller, W.J. C-Src associates with ErbB2 through an interaction between catalytic domains and confers enhanced transforming potential. Mol. Cell. Biol., 2009, 29(21), 5858-5871.
[http://dx.doi.org/10.1128/MCB.01731-08] [PMID: 19704002]
[34]
Blasco, M.T.; Navas, C.; Martín-Serrano, G.; Graña-Castro, O.; Lechuga, C.G.; Martín-Díaz, L.; Djurec, M.; Li, J.; Morales-Cacho, L.; Esteban-Burgos, L.; Perales-Patón, J.; Bousquet-Mur, E.; Castellano, E.; Jacob, H.K.C.; Cabras, L.; Musteanu, M.; Drosten, M.; Ortega, S.; Mulero, F.; Sainz, B., Jr; Dusetti, N.; Iovanna, J.; Sánchez-Bueno, F.; Hidalgo, M.; Khiabanian, H.; Rabadán, R.; Al-Shahrour, F.; Guerra, C.; Barbacid, M. Complete regression of advanced pancreatic ductal adenocarcinomas upon combined inhibition of EGFR and C-RAF. Cancer Cell, 2019, 35(4), 573-587.e6.
[http://dx.doi.org/10.1016/j.ccell.2019.03.002] [PMID: 30975481]
[35]
Fowler, L.R.; Morain, S.R. Schrödinger’s app. Am. J. Law Med., 2020, 46(2-3), 203-218.
[http://dx.doi.org/10.1177/0098858820933495] [PMID: 32659192]
[36]
Huang, L.; Xiao, D.; Wu, T.; Hu, X.; Deng, J.; Yan, X.; Wu, J.; Xu, S.; Yang, X.; Li, G. Phenformin synergistically sensitizes liver cancer cells to sorafenib by downregulating CRAF/ERK and PI3K/AKT/mTOR pathways. Am. J. Transl. Res., 2021, 13(7), 7508-7523.
[PMID: 34377232]
[37]
Vinod, S.K.; Hau, E. Radiotherapy treatment for lung cancer: Current status and future directions. Respirology, 2020, 25(S2)(Suppl. 2), 61-71.
[http://dx.doi.org/10.1111/resp.13870] [PMID: 32516852]
[38]
Guicciardi, M.E.; Malhi, H.; Mott, J.L.; Gores, G.J. Apoptosis and necrosis in the liver. Compr. Physiol., 2013, 3(2), 977-1010.
[http://dx.doi.org/10.1002/cphy.c120020] [PMID: 23720337]
[39]
Kumar, P.; Nagarajan, A.; Uchil, P.D. Analysis of cell viability by the MTT assay. Cold Spring Harb. Protoc., 2018, 2018(6), pdb.prot095505..
[http://dx.doi.org/10.1101/pdb.prot095505] [PMID: 29858338]
[40]
Lin, L.; Ren, L.; Wen, L.; Wang, Y.; Qi, J. Effect of evodiamine on the proliferation and apoptosis of A549 human lung cancer cells. Mol. Med. Rep., 2016, 14(3), 2832-2838.
[http://dx.doi.org/10.3892/mmr.2016.5575] [PMID: 27485202]
[41]
Song, S.; Chen, Z.; Li, S.; Huang, Y.; Wan, Y.; Song, H. Design, synthesis and evaluation of N13-substituted evodiamine derivatives against human cancer cell lines. Molecules, 2013, 18(12), 15750-15768.
[http://dx.doi.org/10.3390/molecules181215750] [PMID: 24352027]
[42]
Blasco, R.B.; Francoz, S.; Santamaría, D.; Cañamero, M.; Dubus, P.; Charron, J.; Baccarini, M.; Barbacid, M. C-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell, 2011, 19(5), 652-663.
[http://dx.doi.org/10.1016/j.ccr.2011.04.002] [PMID: 21514245]
[43]
Karreth, F.A.; Frese, K.K.; DeNicola, G.M.; Baccarini, M.; Tuveson, D.A. C-Raf is required for the initiation of lung cancer by K-Ras(G12D). Cancer Discov., 2011, 1(2), 128-136.
[http://dx.doi.org/10.1158/2159-8290.CD-10-0044] [PMID: 22043453]
[44]
Lito, P.; Saborowski, A.; Yue, J.; Solomon, M.; Joseph, E.; Gadal, S.; Saborowski, M.; Kastenhuber, E.; Fellmann, C.; Ohara, K.; Morikami, K.; Miura, T.; Lukacs, C.; Ishii, N.; Lowe, S.; Rosen, N. Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors. Cancer Cell, 2014, 25(5), 697-710.
[http://dx.doi.org/10.1016/j.ccr.2014.03.011] [PMID: 24746704]
[45]
Wang, H.G.; Rapp, U.R.; Reed, J.C. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell, 1996, 87(4), 629-638.
[http://dx.doi.org/10.1016/S0092-8674(00)81383-5] [PMID: 8929532]
[46]
Panka, D.J.; Atkins, M.B.; Mier, J.W. Targeting the mitogen-activated protein kinase pathway in the treatment of malignant melanoma. Clin. Cancer Res., 2006, 12(7), 2371s-2375s.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2539] [PMID: 16609061]
[47]
Baumann, B.; Weber, C.K.; Troppmair, J.; Whiteside, S.; Israel, A.; Rapp, U.R.; Wirth, T. Raf induces NF-κB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proc. Natl. Acad. Sci. USA, 2000, 97(9), 4615-4620.
[http://dx.doi.org/10.1073/pnas.080583397] [PMID: 10758165]
[48]
Troppmair, J.; Hartkamp, J.; Rapp, U.R. Activation of NF-κB by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene, 1998, 17(6), 685-690.
[http://dx.doi.org/10.1038/sj.onc.1201981] [PMID: 9715269]
[49]
Norris, J.L.; Baldwin, A.S. Jr Oncogenic Ras enhances NF-kappaB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways. J. Biol. Chem., 1999, 274(20), 13841-13846.
[http://dx.doi.org/10.1074/jbc.274.20.13841] [PMID: 10318790]
[50]
Bellacosa, A.; Kumar, C.C.; Cristofano, A.D.; Testa, J.R. Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv. Cancer Res., 2005, 94, 29-86.
[http://dx.doi.org/10.1016/S0065-230X(05)94002-5] [PMID: 16095999]
[51]
Liu, H.W.; Bi, W.T.; Huang, H.T.; Li, R.X.; Xi, Q.; Feng, L.; Bo, W.; Hu, M.; Wen, W.S. Satb1 promotes Schwann cell viability and migration via activation of PI3K/AKT pathway. Eur. Rev. Med. Pharmacol. Sci., 2018, 22(13), 4268-4277.
[PMID: 30024617]
[52]
Siegelin, M.D.; Borczuk, A.C. Epidermal growth factor receptor mutations in lung adenocarcinoma. Lab. Invest., 2014, 94(2), 129-137.
[http://dx.doi.org/10.1038/labinvest.2013.147] [PMID: 24378644]
[53]
Zhou, Y.; Hu, J. Evodiamine induces apoptosis, G2/M cell cycle arrest, and inhibition of cell migration and invasion in human osteosarcoma cells via Raf/MEK/ERK signalling pathway. Med. Sci. Monit., 2018, 24, 5874-5880.
[http://dx.doi.org/10.12659/MSM.909682] [PMID: 30135419]
[54]
Hong, Z.; Wang, Z.; Zhou, B.; Wang, J.; Tong, H.; Liao, Y.; Zheng, P.; Jamshed, M.; Zhang, Q.; Chen, H. Effects of evodiamine on PI3K/Akt and MAPK/ERK signaling pathways in pancreatic cancer cells. Int. J. Oncol., 2020, 56(3), 783-793.
[http://dx.doi.org/10.3892/ijo.2020.4956] [PMID: 31922213]

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