Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Performance of Green Desymmetrization Methods toward Bioactive Cephalostatin Analogues

Author(s): Mansour Nawasreh* and Lubna Tahtamouni

Volume 31, Issue 22, 2024

Published on: 24 July, 2023

Page: [3327 - 3344] Pages: 18

DOI: 10.2174/0929867330666230508145058

Price: $65

Abstract

Since the discovery of cephalostatins, which have shown remarkable activity against human cancer cells, they have attracted the attention of researchers to target the synthesis of such impressive, complicated molecules using the green desymmetrization approach. In the current review, we report the progress in the desymmetrization of symmetrical bis-steroidal pyrazines (BSPs) as an approach toward potentially active anti-- cancer agents, namely cephalostatins/ ritterazines. The achievement of synthesizing a gram-scaled prodrug with comparable activity to the potent natural cephalostatins using green methods is our primary target. These synthetic methods can be scaled up based on the symmetrical coupling (SC) of two steroidal units of the same type. Our secondary target is the discovery of new green pathways that help in structural reconstruction programming toward the total synthesis of at least one potentially active family member. The strategy is based on functional group interconversions with high flexibility and brevity using green selective methods. The introduction of controlling groups using nontrivial reconstruction methodologies forms the backbone of our work. After certain modifications to the symmetrical BSP starting material, the resulting analogs underwent several chemoselective transformations through three main routes in rings F, D, and C. One of these routes is the chemoselective spiroketal opening (ring-F). The second route was the functionalization of the Δ14,15 bond (ring-D), including chlorination/dechlorination, in addition to epoxidation/ oxygenation processes. Finally, the introduction of the C-11 methoxy group as a directing group on ring-C led to several chemoselective transformations. Moreover, certain transformations on C-12 (ring-C), such as methylenation, followed by hydroboration- oxidation, led to a potentially active analog. The alignment of these results directs us toward the targets. Our efforts culminated in preparing effective anti-cancer prodrugs (8, 24, 30, and 31), which are able to overcome cancer drug resistance (chemoresistance) by inducing the atypical endoplasmic reticulum-mediated apoptosis pathway, which works through the release of Smac/Diablo and the activation of caspase-4.

Keywords: Cephalostatin, desymmetrization, bis-steroidal pyrazine, symmetrical coupling, chemoselectivity, ERmediated apoptosis, chemoresistance.

« Previous Next »
[1]
Pettit, G.R.; Inoue, M.; Kamano, Y.; Herald, D.L.; Arm, C.; Dufresne, C.; Christie, N.D.; Schmidt, J.M.; Doubek, D.L.; Krupa, T.S. Antineoplastic agents. 147. Isolation and structure of the powerful cell growth inhibitor cephalostatin 1. J. Am. Chem. Soc., 1988, 110(6), 2006-2007.
[http://dx.doi.org/10.1021/ja00214a078]
[2]
Pettit, G.R.; Xu, J.; Ichihara, Y.; Williams, M.D.; Boyd, M.R. Antineoplastic agents 285. Isolation and structures of cephalostatins 14 and 15. Can. J. Chemistry., 1994, 72(11), 2260-2267.
[http://dx.doi.org/10.1139/v94-288]
[3]
Pettit, G.R.; Xu, J.P.; Schmidt, J.M.; Boyd, M.R. Isolation and structure of the exceptional Pterobranchia human cancer inhibitors cephalostatins 16 and 17. Bioorg. Med. Chem. Lett., 1995, 5(17), 2027-2032.
[http://dx.doi.org/10.1016/0960-894X(95)00346-U]
[4]
Pettit, G.R.; Inoue, M.; Kamano, Y.; Dufresne, C.; Christie, N.; Niven, M.L.; Herald, D.L. Isolation and structure of the hemichordate cell growth inhibitors cephalostatins 2, 3, and 4. J. Chem. Soc. Chem. Commun., 1988, 865–67(13), 865.
[http://dx.doi.org/10.1039/c39880000865]
[5]
Pettit, G.R.; Tan, R.; Xu, J.; Ichihara, Y.; Williams, M.D.; Boyd, M.R. Antineoplastic agents. 398. Isolation and structure elucidation of cephalostatins 18 and 19. J. Nat. Prod., 1998, 61(7), 955-958.
[http://dx.doi.org/10.1021/np9800405] [PMID: 9677284]
[6]
Pettit, GR; Xu, JP; Chapuis, JC The cephalostatins. 24. Isolation, structure, and cancer cell growth inhibition of cephalostatin 20. J. Nat. Prod., 2015, 78, 1446-1450.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00129]
[7]
Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Isolation and structure elucidation of ritterazines B and C, highly cytotoxic dimeric steroidal alkaloids, from the tunicate Ritterella tokioka. J. Org. Chem., 1995, 60(3), 608-614.
[http://dx.doi.org/10.1021/jo00108a024]
[8]
Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Ten more ritterazines, cytotoxic steroidal alkaloids from the tunicate Ritterella tokioka. Tetrahedron, 1995, 51(24), 6707-6716.
[http://dx.doi.org/10.1016/0040-4020(95)00327-5]
[9]
Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Isolation of 13 new ritterazines from the tunicate Ritterella tokioka and chemical transformation of ritterazine B. J. Org. Chem., 1997, 62(13), 4484-4491.
[http://dx.doi.org/10.1021/jo970091r] [PMID: 11671779]
[10]
Kramer, A.; Ullmann, U.; Winterfeldt, E. A short route to cephalostatin analogues. J. Chem. Soc., Perkin Trans. 1, 1993, 1(23), 2865-2867.
[http://dx.doi.org/10.1039/p19930002865]
[11]
Drögemüller, M.; Jautelat, R.; Winterfeldt, E. Directed synthesis of nonsymmetrical bis-steroidal pyrazines and the first biologically active cephalostatin analogues. Angew. Chem. Int. Ed., 1996, 35(1314), 1572-1574.
[http://dx.doi.org/10.1002/anie.199615721]
[12]
Drögemüller, M.; Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Synthesis of cephalostatin analogues by symmetrical and non-symmetrical routes. Eur. J. Org. Chem., 1998, 1998(12), 2811-2831.
[http://dx.doi.org/10.1002/(SICI)1099-0690(199812)1998:12<2811::AID-EJOC2811>3.0.CO;2-M]
[13]
Smith, S.C.; Heathcock, C.H. A convenient procedure for the synthesis of bis-steroidal pyrazines: models for the cephalostatins. J. Org. Chem., 1992, 57(24), 6379-6380.
[http://dx.doi.org/10.1021/jo00050a002]
[14]
Heathcock, C.H.; Smith, S.C. Synthesis and biological activity Of unsymmetrical bis-steroidal pyrazines related to the cytotoxic marine natural product cephalostatin 1. J. Org. Chem., 1994, 59(22), 6828-6839.
[http://dx.doi.org/10.1021/jo00101a052]
[15]
LaCour, T.G.; Guo, C.; Bhandaru, S.; Boyd, M.R.; Fuchs, P.L. Interphylal product splicing: The first total syntheses of cephalostatin 1, the north hemisphere of ritterazine G, and the highly active hybrid analogue, ritterostatin GN1N1. J. Am. Chem. Soc., 1998, 120(4), 692-707.
[http://dx.doi.org/10.1021/ja972160p]
[16]
Fortner, K.C.; Kato, D.; Tanaka, Y.; Shair, M.D. Enantioselective synthesis of (+)-cephalostatin 1. J. Am. Chem. Soc., 2010, 132(1), 275-280.
[http://dx.doi.org/10.1021/ja906996c] [PMID: 19968285]
[17]
Jeong, J.U.; Guo, C.; Fuchs, P.L. Synthesis of the south unit of cephalostatin. 7. Total syntheses of (+)-cephalostatin 7, (+)-cephalostatin 12, and (+)-ritterazine K 1. J. Am. Chem. Soc., 1999, 121(10), 2071-2084.
[http://dx.doi.org/10.1021/ja9817141]
[18]
Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Cephalostatin analogues--synthesis and biological activity. Fortschr. Chem. Org. Naturst., 2004, 87, 1-80.
[http://dx.doi.org/10.1007/978-3-7091-0581-8_1] [PMID: 15079895]
[19]
Nawasreh, M. Novel reactions in the cephalostatin series. Curr. Org. Chem., 2009, 13(4), 407-420.
[http://dx.doi.org/10.2174/138527209787582286]
[20]
Iglesias-Arteaga, M.A.; Morzycki, J.W. Cephalostatins and ritterazines. Alkaloids Chem. Biol., 2013, 72, 153-279.
[http://dx.doi.org/10.1016/B978-0-12-407774-4.00002-9] [PMID: 24712099]
[21]
Pettit, G.R.; Kamano, Y.; Inoue, M.; Dufresne, C.; Boyd, M.R.; Herald, C.L.; Schmidt, J.M.; Doubek, D.L.; Christie, N.D. Antineoplastic agents. 214. Isolation and structure of cephalostatins 7-9. J. Org. Chem., 1992, 57(2), 429-431.
[http://dx.doi.org/10.1021/jo00028a007]
[22]
Bäsler, S.; Brunck, A.; Jautelat, R.; Winterfeldt, E. Synthesis of cytostatic tetradecacyclic pyrazines and a novel reduction-oxidation sequence for spiroketal opening in sapogenins. Helv. Chim. Acta, 2000, 83(8), 1854-1880.
[http://dx.doi.org/10.1002/1522-2675(20000809)83:8<1854::AID-HLCA1854>3.0.CO;2-4]
[23]
Nawasreh, M.; Winterfeldt, E. Novel routes to nonsymmetric cephalostatin analogous. Curr. Org. Chem., 2003, 7, 649-658.
[http://dx.doi.org/10.2174/1385272033486774]
[24]
Nawasreh, M. Chemo-, regio-, and stereoselectivity of F-ring opening reactions in the cephalostatin series. Bioorg. Med. Chem., 2008, 16(1), 255-265.
[http://dx.doi.org/10.1016/j.bmc.2007.09.043] [PMID: 17981469]
[25]
Nawasreh, M.M. Selective transformations of cephalostatin analogues. Pure Appl. Chem., 2011, 83(3), 699-707.
[http://dx.doi.org/10.1351/PAC-CON-10-08-15]
[26]
Nawasreh, M. Progress in chemo- and regioselective transformations of symmetrical cephalostatin analogues. Lett. Org. Chem., 2018, 15(2), 155-161.
[http://dx.doi.org/10.2174/1570178614666170907113121]
[27]
Salvador, J.A.R.; Carvalho, J.F.S.; Neves, M.A.C.; Silvestre, S.M.; Leitão, A.J.; Silva, M.M.C.; Sá e Melo, M.L. Anticancer steroids: Linking natural and semi-synthetic compounds. Nat. Prod. Rep., 2013, 30(2), 324-374.
[http://dx.doi.org/10.1039/C2NP20082A] [PMID: 23151898]
[28]
Nawasreh, M.; Kirschning, A.; Duddeck, H.; Dräger, G.; Fenske, D. Novel double functional protection of cephalostatin analogues using a gas-free chlorination method. Heliyon, 2020, 6(1), e03025.
[http://dx.doi.org/10.1016/j.heliyon.2019.e03025] [PMID: 31909240]
[29]
Holland, H.L.; Chenchaiah, P.C.; Thomas, E.M.; Mader, B.; Dennis, M.J. Microbial hydroxylation of steroids. 9. Epoxidation of Δ 6 -3-ketosteroids by Rhizopus arrhizus ATCC 11145, and the mechanism of the 6β hydroxylase enzyme. Can. J. Chem., 1984, 62(12), 2740-2747.
[http://dx.doi.org/10.1139/v84-466]
[30]
Kurosawa, Y.; Hayano, M.; Bloom, B.M. The epoxidation of unsaturated steroids. Agric. Biol. Chem., 1961, 25(11), 838-843.
[http://dx.doi.org/10.1080/00021369.1961.10857887]
[31]
May, S.W. Enzymatic epoxidation reactions. Enzyme Microb. Technol., 1979, 1(1), 15-22.
[http://dx.doi.org/10.1016/0141-0229(79)90005-X]
[32]
Nawasreh, M. Dissertation-Hannover University, 2000.
[33]
Nawasreh, M.M. Novel epoxidation/oxygenation method toward bioactive cephalostatins using common alkaline metals. ChemistrySelect, 2022, 7(6), e202103756.
[http://dx.doi.org/10.1002/slct.202103756]
[34]
Nawasreh, M. Chemo- and regioselective hydroboration of Δ14,15 in certain cephalostatin analogue. Chin. Chem. Lett., 2008, 19(12), 1391-1394.
[http://dx.doi.org/10.1016/j.cclet.2008.09.055]
[35]
Liew, S.K.; Malagobadan, S.; Arshad, N.M.; Nagoor, N.H. A review of the structure–activity relationship of natural and synthetic antimetastatic compounds. Biomolecules, 2020, 10(1), 138.
[http://dx.doi.org/10.3390/biom10010138] [PMID: 31947704]
[36]
Nawasreh, M.M.; Alzyoud, E.I.; Al-Mazaydeh, Z.A.; Rammaha, M.S.; Yasin, S.R.; Tahtamouni, L.H. Biological activity and apoptotic signaling pathway of C11-functionalized cephalostatin 1 analogues. Steroids, 2020, 158, 108602.
[http://dx.doi.org/10.1016/j.steroids.2020.108602] [PMID: 32092307]
[37]
Nawasreh, M. Stereoselective synthesis of bis-steroidal pyrazine derivatives. Nat. Prod. Res., 2007, 21(2), 91-99.
[http://dx.doi.org/10.1080/14786410500059243] [PMID: 17380598]
[38]
Tahtamouni, L.H.; Nawasreh, M.M.; Al-Mazaydeh, Z.A.; Al-Khateeb, R.A.; Abdellatif, R.N.; Bawadi, R.M.; Bamburg, J.R.; Yasin, S.R. Cephalostatin 1 analogues activate apoptosis via the endoplasmic reticulum stress signaling pathway. Eur. J. Pharmacol., 2018, 818, 400-409.
[http://dx.doi.org/10.1016/j.ejphar.2017.11.025] [PMID: 29154934]
[39]
Nawasreh, M.M. Novel Applications of Alkaline Metals in Cephalostatin Theme. 2023.
[40]
Assessing national capacity for the prevention and control of noncommunicable diseases: report of the 2019 global survey. Geneva, World Health Organization, 2020.
[41]
Debela, D.T.; Muzazu, S.G.Y.; Heraro, K.D.; Ndalama, M.T.; Mesele, B.W.; Haile, D.C.; Kitui, S.K.; Manyazewal, T. New approaches and procedures for cancer treatment: Current perspectives. SAGE Open Med., 2021, 9.
[http://dx.doi.org/10.1177/20503121211034366] [PMID: 34408877]
[42]
DeVita, V.T., Jr; Chu, E. A history of cancer chemotherapy. Cancer Res., 2008, 68(21), 8643-8653.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-6611] [PMID: 18974103]
[43]
Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of multidrug resistance in cancer chemotherapy. Int. J. Mol. Sci., 2020, 21(9), 3233.
[http://dx.doi.org/10.3390/ijms21093233] [PMID: 32370233]
[44]
Hassan, O.M.;Razzak Mahmood, A.A.;Hamzah, A.H.; Tahtamouni, L.H.Design, synthesis, and molecular docking studies of 5-bromoindole-2-carboxylic acid hydrazone derivatives: In vitro anticancer and VEGFR-2 inhibitory effects. Chemistry Select, 2022, 7(46), e202203726.
[http://dx.doi.org/10.1002/slct.202203726]
[45]
Alsaad, H.; Kubba, A.; Tahtamouni, L.H.; Hamzah, A.H. Synthesis, docking study, and structure activity relationship of novel anti-tumor 1, 2, 4 triazole derivatives incorporating 2-(2, 3- dimethyl aminobenzoic acid) moiety. Pharmacia, 2022, 69(2), 415-428.
[http://dx.doi.org/10.3897/pharmacia.69.e83158]
[46]
Yaseen, Y.; Kubba, A.; Shihab, W.; Tahtamouni, L. Synthesis, docking study, and structure-activity relationship of novel niflumic acid derivatives acting as anticancer agents by inhibiting VEGFR or EGFR tyrosine kinase activities. Pharmacia, 2022, 69(3), 595-614.
[http://dx.doi.org/10.3897/pharmacia.69.e86504]
[47]
Singh, R.; Letai, A.; Sarosiek, K. Regulation of apoptosis in health and disease: The balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol., 2019, 20(3), 175-193.
[http://dx.doi.org/10.1038/s41580-018-0089-8] [PMID: 30655609]
[48]
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[49]
Dirsch, V.M.; Müller, I.M.; Eichhorst, S.T.; Pettit, G.R.; Kamano, Y.; Inoue, M.; Xu, J.P.; Ichihara, Y.; Wanner, G.; Vollmar, A.M. Cephalostatin 1 selectively triggers the release of Smac/DIABLO and subsequent apoptosis that is characterized by an increased density of the mitochondrial matrix. Cancer Res., 2003, 63(24), 8869-8876.
[PMID: 14695204]
[50]
Dirsch, V.M.; Vollmar, A.M. Cephalostatin 1-induced apoptosis in tumor cells. In: Application of Apoptosis to Cancer Treatment; Springer: Dordrecht, 2005.
[http://dx.doi.org/10.1007/1-4020-3302-8_9]
[51]
Liebezeit, G. Aquaculture of “non-food organisms” for natural substance production. Adv. Biochem. Eng. Biotechnol., 2005, 97, 1-28.
[http://dx.doi.org/10.1007/b135821] [PMID: 16261804]
[52]
Lee, S.; LaCour, T.G.; Fuchs, P.L. Chemistry of trisdecacyclic pyrazine antineoplastics: The cephalostatins and ritterazines. Chem. Rev., 2009, 109(6), 2275-2314.
[http://dx.doi.org/10.1021/cr800365m] [PMID: 19438206]
[53]
Imperatore, C.; Aiello, A.; D’Aniello, F.; Senese, M.; Menna, M. Alkaloids from marine invertebrates as important leads for anticancer drugs discovery and development. Molecules, 2014, 19(12), 20391-20423.
[http://dx.doi.org/10.3390/molecules191220391] [PMID: 25490431]
[54]
Rudy, A.; López-Antón, N.; Dirsch, V.M.; Vollmar, A.M. The cephalostatin way of apoptosis. J. Nat. Prod., 2008, 71(3), 482-486.
[http://dx.doi.org/10.1021/np070534e] [PMID: 18257532]
[55]
von Schwarzenberg, K.; Vollmar, A.M. Targeting apoptosis pathways by natural compounds in cancer: Marine compounds as lead structures and chemical tools for cancer therapy. Cancer Lett., 2013, 332(2), 295-303.
[http://dx.doi.org/10.1016/j.canlet.2010.07.004] [PMID: 20673697]
[56]
Bahar, E.; Kim, J.Y.; Yoon, H. Chemotherapy resistance explained through endoplasmic reticulum stress-dependent signaling. Cancers, 2019, 11(3), 338.
[http://dx.doi.org/10.3390/cancers11030338] [PMID: 30857233]
[57]
Sequist, L.V.; Waltman, B.A.; Dias-Santagata, D.; Digumarthy, S.; Turke, A.B.; Fidias, P.; Bergethon, K.; Shaw, A.T.; Gettinger, S.; Cosper, A.K.; Akhavanfard, S.; Heist, R.S.; Temel, J.; Christensen, J.G.; Wain, J.C.; Lynch, T.J.; Vernovsky, K.; Mark, E.J.; Lanuti, M.; Iafrate, A.J.; Mino-Kenudson, M.; Engelman, J.A. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med., 2011, 3(75), 75ra26.
[http://dx.doi.org/10.1126/scitranslmed.3002003] [PMID: 21430269]
[58]
Yu, H.A.; Arcila, M.E.; Rekhtman, N.; Sima, C.S.; Zakowski, M.F.; Pao, W.; Kris, M.G.; Miller, V.A.; Ladanyi, M.; Riely, G.J. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res., 2013, 19(8), 2240-2247.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-2246] [PMID: 23470965]
[59]
Sicari, D.; Delaunay-Moisan, A.; Combettes, L. A guide to assessing endoplasmic reticulum homeostasis and stress in mammalian systems. FEBS J, 2019, 287(1), 27-42.
[http://dx.doi.org/10.1111/febs.15107]
[60]
Lin, Y.; Jiang, M.; Chen, W.; Zhao, T.; Wei, Y. Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed. Pharmacother., 2019, 118, 109249.
[http://dx.doi.org/10.1016/j.biopha.2019.109249] [PMID: 31351428]
[61]
Avril, T.; Vauléon, E.; Chevet, E. Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis, 2017, 6(8), e373.
[http://dx.doi.org/10.1038/oncsis.2017.72] [PMID: 28846078]
[62]
Yamamuro, A.; Kishino, T.; Ohshima, Y.; Yoshioka, Y.; Kimura, T.; Kasai, A.; Maeda, S. Caspase-4 directly activates caspase-9 in endoplasmic reticulum stress-induced apoptosis in SH-SY5Y cells. J. Pharmacol. Sci., 2011, 115(2), 239-243.
[http://dx.doi.org/10.1254/jphs.10217SC]
[63]
Hu, P.; Han, Z.; Couvillon, A.D.; Exton, J.H. Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J. Biol. Chem., 2004, 279(47), 49420-49429.
[http://dx.doi.org/10.1074/jbc.M407700200] [PMID: 15339911]
[64]
Khaled, J.; Kopsida, M.; Lennernäs, H.; Heindryckx, F. Drug resistance and endoplasmic reticulum stress in hepatocellular carcinoma. Cells, 2022, 11(4), 632.
[http://dx.doi.org/10.3390/cells11040632] [PMID: 35203283]
[65]
Oakes, S.A. Endoplasmic reticulum stress signaling in cancer cells. Am. J. Pathol., 2020, 190(5), 934-946.
[http://dx.doi.org/10.1016/j.ajpath.2020.01.010] [PMID: 32112719]
[66]
Harrington, P.E.; Biswas, K.; Malwitz, D.; Tasker, A.S.; Mohr, C.; Andrews, K.L.; Dellamaggiore, K.; Kendall, R.; Beckmann, H.; Jaeckel, P.; Materna-Reichelt, S.; Allen, J.R.; Lipford, J.R. Unfolded protein response in cancer: IRE1α inhibition by selective kinase ligands does not impair tumor cell viability. ACS Med. Chem. Lett., 2015, 6(1), 68-72.
[http://dx.doi.org/10.1021/ml500315b] [PMID: 25589933]
[67]
Pytel, D.; Gao, Y.; Mackiewicz, K.; Katlinskaya, Y.V.; Staschke, K.A.; Paredes, M.C.G.; Yoshida, A.; Qie, S.; Zhang, G.; Chajewski, O.S.; Wu, L.; Majsterek, I.; Herlyn, M.; Fuchs, S.Y.; Diehl, J.A. PERK is a haploinsufficient tumor suppressor: Gene dose determines tumor-suppressive versus tumor promoting properties of PERK in melanoma. PLoS Genet., 2016, 12(12), e1006518.
[http://dx.doi.org/10.1371/journal.pgen.1006518] [PMID: 27977682]
[68]
Wu, J.; Chen, S.; Liu, H.; Zhang, Z.; Ni, Z.; Chen, J.; Yang, Z.; Nie, Y.; Fan, D. Tunicamycin specifically aggravates ER stress and overcomes chemoresistance in multidrug-resistant gastric cancer cells by inhibiting N-glycosylation. J. Exp. Clin. Cancer Res., 2018, 37(1), 272.
[http://dx.doi.org/10.1186/s13046-018-0935-8] [PMID: 30413206]

Rights & Permissions Print Cite
Article Metrics
17
1
© 2024 Bentham Science Publishers | Privacy Policy