Login Register Cart 0
Generic placeholder image

Current Organic Synthesis

Editor-in-Chief

ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

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

A Facile Total Synthesis of Kilogram-Scale Production of SKLB1039: A Novel and Selective Hexahydroisoquinolin-Containing EZH2 Inhibitor

Author(s): Qiang Feng, Qiangsheng Zhang, Hualong He, Lidan Zhang, Bo Chang, Luoting Yu* and Xiaoling Zhang*

Volume 19, Issue 5, 2022

Published on: 21 April, 2022

Page: [583 - 590] Pages: 8

DOI: 10.2174/1570179419666220107161257

Price: $65

Abstract

Background: SKLB1039 is a potent, highly selective, and orally bioavailable EZH2 inhibitor, which significantly inhibited breast tumor growth and metastasis in pre-clinical studies. In a previously reported synthesis of SKLB1039, the yields of several steps were low, which led to an overall yield of less than 10%. In addition, flash chromatography was required for the purification of several intermediates using this route.

Objective: To optimize the synthesis and establish an efficient commercial-scale method for the production of SKLB1039.

Methods: The reaction time, solvent, reactant ratio, temperature, and mode of addition of reactants in the reductive amination, hydrolysis, hexahydroisoquinoline formation, hydrogenolysis, condensation and Suzuki crosscoupling reactions were optimized.

Results: A chromatography-free seven-step process starting from a commercially available material was developed that afforded SKLB1039 in 36% overall yield with > 99% purity.

Conclusion: A cost-effective, high-yielding, and convergent kilo-scale synthesis for the EZH2 inhibitor SKLB1039 was developed. The operation was simple, and the pure product was easily obtained without column chromatography. This method will be economical and convenient for the subsequent industrial scale-up production of SKLB1039, which will be conducive for this promising EZH2 inhibitor to enter clinical studies of its antitumor effects.

Keywords: EZH2 inhibitor, scale-up production, suzuki-miyaura cross coupling, antitumor, kilo-scale synthesis, EzH2 inhibitor.

« Previous Next »
Graphical Abstract

[1]
Cao, R.; Wang, L.; Wang, H.; Xia, L.; Erdjument-Bromage, H.; Tempst, P.; Jones, R.S.; Zhang, Y. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science, 2002, 298(5595), 1039-1043.
[http://dx.doi.org/10.1126/science.1076997] [PMID: 12351676]
[2]
Kuzmichev, A.; Nishioka, K.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D. Histone methyltransferase activity associated with a human multiprotein complex con-taining the Enhancer of Zeste protein. Genes Dev., 2002, 16(22), 2893-2905.
[http://dx.doi.org/10.1101/gad.1035902] [PMID: 12435631]
[3]
Simon, J.A.; Lange, C.A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res., 2008, 647(1-2), 21-29.
[http://dx.doi.org/10.1016/j.mrfmmm.2008.07.010] [PMID: 18723033]
[4]
Pasini, D.; Bracken, A.P.; Hansen, J.B.; Capillo, M.; Helin, K. The polycomb group protein Suz12 is required for embryonic stem cell differentiation. Mol. Cell. Biol., 2007, 27(10), 3769-3779.
[http://dx.doi.org/10.1128/MCB.01432-06] [PMID: 17339329]
[5]
Raaphorst, F.M.; van Kemenade, F.J.; Blokzijl, T.; Fieret, E.; Hamer, K.M.; Satijn, D.P.; Otte, A.P.; Meijer, C.J. Coexpression of BMI-1 and EZH2 polycomb group genes in Reed-Sternberg cells of Hodgkin’s disease. Am. J. Pathol., 2000, 157(3), 709-715.
[http://dx.doi.org/10.1016/S0002-9440(10)64583-X] [PMID: 10980109]
[6]
Visser, H.P.J.; Gunster, M.J.; Kluin-Nelemans, H.C.; Manders, E.M.M.; Raaphorst, F.M.; Meijer, C.J.L.M.; Willemze, R.; Otte, A.P. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br. J. Haematol., 2001, 112(4), 950-958.
[http://dx.doi.org/10.1046/j.1365-2141.2001.02641.x] [PMID: 11298590]
[7]
Tamgue, O.; Chai, C.S.; Hao, L.; Zambe, J.C.; Huang, W.W.; Zhang, B.; Lei, M.; Wei, Y.M. Triptolide inhibits histone methyltransferase EZH2 and modulates the expres-sion of its target genes in prostate cancer cells. Asian Pac. J. Cancer Prev., 2013, 14(10), 5663-5669.
[http://dx.doi.org/10.7314/APJCP.2013.14.10.5663] [PMID: 24289559]
[8]
Morin, R.D.; Johnson, N.A.; Severson, T.M.; Mungall, A.J.; An, J.; Goya, R.; Paul, J.E.; Boyle, M.; Woolcock, B.W.; Kuchenbauer, F.; Yap, D.; Humphries, R.K.; Griffith, O.L.; Shah, S.; Zhu, H.; Kimbara, M.; Shashkin, P.; Charlot, J.F.; Tcherpakov, M.; Corbett, R.; Tam, A.; Varhol, R.; Smailus, D.; Moksa, M.; Zhao, Y.; Delaney, A.; Qian, H.; Birol, I.; Schein, J.; Moore, R.; Holt, R.; Horsman, D.E.; Connors, J.M.; Jones, S.; Aparicio, S.; Hirst, M.; Gascoyne, R.D.; Marra, M.A. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet., 2010, 42(2), 181-185.
[http://dx.doi.org/10.1038/ng.518] [PMID: 20081860]
[9]
Morin, R.D.; Mendez-Lago, M.; Mungall, A.J.; Goya, R.; Mungall, K.L.; Corbett, R.D.; Johnson, N.A.; Severson, T.M.; Chiu, R.; Field, M.; Jackman, S.; Krzywinski, M.; Scott, D.W.; Trinh, D.L.; Tamura-Wells, J.; Li, S.; Firme, M.R.; Rogic, S.; Griffith, M.; Chan, S.; Yakovenko, O.; Meyer, I.M.; Zhao, E.Y.; Smailus, D.; Moksa, M.; Chit-taranjan, S.; Rimsza, L.; Brooks-Wilson, A.; Spinelli, J.J.; Ben-Neriah, S.; Meissner, B.; Woolcock, B.; Boyle, M.; McDonald, H.; Tam, A.; Zhao, Y.; Delaney, A.; Zeng, T.; Tse, K.; Butterfield, Y.; Birol, I.; Holt, R.; Schein, J.; Horsman, D.E.; Moore, R.; Jones, S.J.; Connors, J.M.; Hirst, M.; Gascoyne, R.D.; Marra, M.A. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature, 2011, 476(7360), 298-303.
[http://dx.doi.org/10.1038/nature10351] [PMID: 21796119]
[10]
McCabe, M.T.; Graves, A.P.; Ganji, G.; Diaz, E.; Halsey, W.S.; Jiang, Y.; Smitheman, K.N.; Ott, H.M.; Pappalardi, M.B.; Allen, K.E.; Chen, S.B.; Della Pietra, A., III; Dul, E.; Hughes, A.M.; Gilbert, S.A.; Thrall, S.H.; Tummino, P.J.; Kruger, R.G.; Brandt, M.; Schwartz, B.; Creasy, C.L. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc. Natl. Acad. Sci. USA, 2012, 109(8), 2989-2994.
[http://dx.doi.org/10.1073/pnas.1116418109] [PMID: 22323599]
[11]
McCabe, M.T.; Ott, H.M.; Ganji, G.; Korenchuk, S.; Thompson, C.; Van Aller, G.S.; Liu, Y.; Graves, A.P.; Della Pietra, A., III; Diaz, E.; LaFrance, L.V.; Mellinger, M.; Duquenne, C.; Tian, X.; Kruger, R.G.; McHugh, C.F.; Brandt, M.; Miller, W.H.; Dhanak, D.; Verma, S.K.; Tummino, P.J.; Creasy, C.L. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature, 2012, 492(7427), 108-112.
[http://dx.doi.org/10.1038/nature11606] [PMID: 23051747]
[12]
Zhang, Q.; Hu, X.; Li, L.; Zhang, L.; Wan, G.; Feng, Q.; Zhu, Y.; Wang, N.; Liu, Z.; Yu, L. The discovery of SKLB-0335 as a paralog-selective EZH2 covalent inhibitor. Chem. Commun. (Camb.), 2021, 57(24), 3006-3009.
[http://dx.doi.org/10.1039/D0CC04670A] [PMID: 33623946]
[13]
Kuntz, K.W.; Campbell, J.E.; Keilhack, H.; Pollock, R.M.; Knutson, S.K.; Porter-Scott, M.; Richon, V.M.; Sneeringer, C.J.; Wigle, T.J.; Allain, C.J.; Majer, C.R.; Moyer, M.P.; Copeland, R.A.; Chesworth, R. the importance of being me: magic methyls, methyltransferase inhibitors, and the discovery of tazemetostat. J. Med. Chem., 2016, 59(4), 1556-1564.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01501] [PMID: 26769278]
[14]
Vaswani, R.G.; Gehling, V.S.; Dakin, L.A.; Cook, A.S.; Nasveschuk, C.G.; Duplessis, M.; Iyer, P.; Balasubramanian, S.; Zhao, F.; Good, A.C.; Campbell, R.; Lee, C.; Cantone, N.; Cummings, R.T.; Normant, E.; Bellon, S.F.; Albrecht, B.K.; Harmange, J.C.; Trojer, P.; Audia, J.E.; Zhang, Y.; Justin, N.; Chen, S.; Wilson, J.R.; Gamblin, S.J. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-Cell lymphomas. J. Med. Chem., 2016, 59(21), 9928-9941.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01315] [PMID: 27739677]
[15]
Zhang, L.; Song, X.; Wang, N.; Zhao, L.; Feng, Q.; You, X.; Peng, C.; Gao, T.; Xiong, M.; He, B.; Gao, C.; Luo, Y.; Xu, Y.; Zhang, Q.; Yu, L. Design, synthesis and biologi-cal evaluation of novel 1-methyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinolins as potential EZH2 inhibitors. RSC Advances, 2015, 5(33), 25967-25978.
[http://dx.doi.org/10.1039/C5RA02365C]
[16]
Song, X.; Gao, T.; Wang, N.; Feng, Q.; You, X.; Ye, T.; Lei, Q.; Zhu, Y.; Xiong, M.; Xia, Y.; Yang, F.; Shi, Y.; Wei, Y.; Zhang, L.; Yu, L. Corrigendum: Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer. Sci. Rep., 2016, 6, 24893.
[http://dx.doi.org/10.1038/srep24893] [PMID: 27128979]
[17]
Gao, T.T.; Zhang, L.D.; Zhu, Y.X.; Song, X.J.; Feng, Q.; Lei, Q.; Shi, S.X.; Deng, H.X.; Xiong, M.H.; You, X.Y.; Zuo, W.Q.; Liu, L.; Peng, C.T.; Wang, N.Y.; Ye, T.H.; Xia, Y.; Yu, L.T. ZLD1122, a novel EZH2 and EZH1 small molecular inhibitor, blocks H3K27 methylation and diffuse large B cell lymphoma cell growth. RSC Advances, 2016, 6(34), 28512-28521.
[http://dx.doi.org/10.1039/C6RA00618C]

Rights & Permissions Print Cite
Article Metrics
13
1
© 2024 Bentham Science Publishers | Privacy Policy