A Facile Synthesis of Ligands for the von Hippel–Lindau E3 Ligase

Christian Steinebach; Sabine Anna Voell; Lan Phuong Vu; Aleša Bricelj; Izidor Sosič; Gregor Schnakenburg; Michael Gütschow

doi:10.1055/s-0040-1707400

Synthesis, Table of Contents

Synthesis 2020; 52(17): 2521-2527
DOI: 10.1055/s-0040-1707400

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A Facile Synthesis of Ligands for the von Hippel–Lindau E3 Ligase

Authors

Christian Steinebach

^aPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany Email: guetschow@uni-bonn.de
Sabine Anna Voell

^aPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany Email: guetschow@uni-bonn.de
Lan Phuong Vu

^aPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany Email: guetschow@uni-bonn.de
Aleša Bricelj

^bFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Izidor Sosič

^bFaculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
Gregor Schnakenburg

^cInstitute of Inorganic Chemistry, University of Bonn, Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
Michael Gütschow ∗

^aPharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany Email: guetschow@uni-bonn.de

Abstract

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Abstract

The proteolysis-targeting chimeras (PROTACs) have become an integral part of different stages of drug discovery. This growing field, therefore, benefits from advancements in all segments of the design of these compounds. Herein, an efficient and optimized synthetic protocol to various von Hippel-Lindau (VHL) ligands is presented, which enables easy access to multigram quantities of these essential PROTAC building blocks. Moreover, the elaborated synthesis represents a straightforward approach to further explore the chemical space of VHL ligands.

Key words

PROTACs - protein degradation - von Hippel–Lindau - VHL - E3 ligase - reductive amination - protecting group

Full Text

References

References

1a Churcher I. J. Med. Chem. 2018; 61: 444
1b An S, Fu L. EBioMedicine 2018; 36: 553
1c Maniaci C, Ciulli A. Curr. Opin. Chem. Biol. 2019; 52: 145
1d Burslem GM, Crews CM. Cell 2020; 181: 102
1e Verma R, Mohl D, Deshaies RJ. Mol. Cell 2020; 77: 446

2a Zengerle M, Chan K.-H, Ciulli A. ACS Chem. Biol. 2015; 10: 1770
2b Lai AC, Toure M, Hellerschmied D, Salami J, Jaime-Figueroa S, Ko E, Hines J, Crews CM. Angew. Chem. Int. Ed. 2016; 55: 807
2c Gadd MS, Testa A, Lucas X, Chan K.-H, Chen W, Lamont DJ, Zengerle M, Ciulli A. Nat. Chem. Biol. 2017; 13: 514
2d Schiedel M, Herp D, Hammelmann S, Swyter S, Lehotzky A, Robaa D, Oláh J, Ovádi J, Sippl W, Jung M. J. Med. Chem. 2018; 61: 482
2e Steinebach C, Kehm H, Lindner S, Vu LP, Köpff S, López Mármol Á, Weiler C, Wagner KG, Reichenzeller M, Krönke J, Gütschow M. Chem. Commun. 2019; 55: 1821
2f Testa A, Hughes SJ, Lucas X, Wright JE, Ciulli A. Angew. Chem. Int. Ed. 2020; 59: 1727
2g Steinebach C, Ng YL. D, Sosič I, Lee C.-S, Chen S, Lindner S, Vu LP, Bricelj A, Haschemi R, Monschke M, Steinwarz E, Wagner KG, Bendas G, Luo J, Gütschow M, Krönke J. Chem. Sci. 2020; 11: 3474

3a Khan S, Zhang X, Lv D, Zhang Q, He Y, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand JS, Pei J, Zhang W, Sharma A, McCurdy CR, Kuruvilla VM, Baran N, Ferrando AA, Kim Y, Rogojina A, Houghton PJ, Huang G, Hromas R, Konopleva M, Zheng G, Zhou D. Nat. Med. 2019; 25: 1938
3b Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhöfer-Wölfer K, Wöhrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu M.-Y, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB, Ciulli A. Nat. Chem. Biol. 2019; 15: 672

4a Lohbeck J, Miller AK. Bioorg. Med. Chem. Lett. 2016; 26: 5260
4b Papatzimas J, Gorobets E, Brownsey D, Maity R, Bahlis N, Derksen D. Synlett 2017; 28: 2881
4c Wurz RP, Dellamaggiore K, Dou H, Javier N, Lo M.-C, McCarter JD, Mohl D, Sastri C, Lipford JR, Cee VJ. J. Med. Chem. 2018; 61: 453
4d Qiu X, Sun N, Kong Y, Li Y, Yang X, Jiang B. Org. Lett. 2019; 21: 3838
4e Steinebach C, Sosič I, Lindner S, Bricelj A, Kohl F, Ng YL. D, Monschke M, Wagner KG, Krönke J, Gütschow M. Med. Chem. Commun. 2019; 10: 1037

5a Frost J, Galdeano C, Soares P, Gadd MS, Grzes KM, Ellis L, Epemolu O, Shimamura S, Bantscheff M, Grandi P, Read KD, Cantrell DA, Rocha S, Ciulli A. Nat. Commun. 2016; 7: 13312
5b Soares P, Gadd MS, Frost J, Galdeano C, Ellis L, Epemolu O, Rocha S, Read KD, Ciulli A. J. Med. Chem. 2018; 61: 599
5c Testa A, Lucas X, Castro GV, Chan K.-H, Wright JE, Runcie AC, Gadd MS, Harrison WT. A, Ko E.-J, Fletcher D, Ciulli A. J. Am. Chem. Soc. 2018; 140: 9299
5d Soares P, Lucas X, Ciulli A. Bioorg. Med. Chem. 2018; 26: 2992
5e Lucas X, Van Molle I, Ciulli A. J. Med. Chem. 2018; 61: 7387
5f de Castro GV, Ciulli A. Chem. Commun. 2019; 55: 1482
5g Han X, Wang C, Qin C, Xiang W, Fernandez-Salas E, Yang C.-Y, Wang M, Zhao L, Xu T, Chinnaswamy K, Delproposto J, Stuckey J, Wang S. J. Med. Chem. 2019; 62: 941

6a Maniaci C, Hughes SJ, Testa A, Chen W, Lamont DJ, Rocha S, Alessi DR, Romeo R, Ciulli A. Nat. Commun. 2017; 8: 830
6b Zoppi V, Hughes SJ, Maniaci C, Testa A, Gmaschitz T, Wieshofer C, Koegl M, Riching KM, Daniels DL, Spallarossa A, Ciulli A. J. Med. Chem. 2019; 62: 699
6c Smith BE, Wang SL, Jaime-Figueroa S, Harbin A, Wang J, Hamman BD, Crews CM. Nat. Commun. 2019; 10: 131

7 Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I, Hewitt S, Dias DM, Ciulli A. J. Med. Chem. 2014; 57: 8657
8 Johnson CN, Adelinet C, Berdini V, Beke L, Bonnet P, Brehmer D, Calo F, Coyle JE, Day PJ, Frederickson M, Freyne EJ. E, Gilissen RA. H. J, Hamlett CC. F, Howard S, Meerpoel L, Mevellec L, McMenamin R, Pasquier E, Patel S, Rees DC, Linders JT. M. ACS Med. Chem. Lett. 2015; 6: 31
9 Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL, Smith IE, Miah AH, Harling JD, Crews CM. ACS Chem. Biol. 2015; 10: 1831
10 For the characterization of the O-acyl side product occurring during the coupling of phenol 6d with Boc-Hyp-OH, see Supporting Information.
11 Kaburagi Y, Kishi Y. Org. Lett. 2007; 9: 723

12a Buckley DL, Van Molle I, Gareiss PC, Tae HS, Michel J, Noblin DJ, Jorgensen WL, Ciulli A, Crews CM. J. Am. Chem. Soc. 2012; 134: 4465
12b Tovell H, Testa A, Maniaci C, Zhou H, Prescott AR, Macartney T, Ciulli A, Alessi DR. ACS Chem. Biol. 2019; 14: 882

13 The X-ray crystallographic data collection for compounds 14 was performed on a Bruker X8-Kappa ApexII diffractometer at 100(2) K. The diffractometer was equipped with a low-temperature device (Kryoflex I, Bruker AXS) and used Mo-K _α radiation (λ = 0.71073 Å). Intensities were measured by fine-slicing ϕ- and ω-scans and corrected for background, polarization, and Lorentz effects. Semiempirical absorption corrections were applied for all data sets by using Bruker’s SADABS program. The structures were solved by direct methods and refined anisotropically by the least-squares procedure implemented in the ShelX-2014/7 program system. Hydrogen atoms were included isotopically using the riding model on the bound carbon atoms. CCDC 1986177 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
14 For the feasible synthesis of aldehyde 4d from 3-bromophenol or 4-bromosalicylic acid, see Supporting Information.

15a Raina K, Lu J, Qian Y, Altieri M, Gordon D, Rossi AM. K, Wang J, Chen X, Dong H, Siu K, Winkler JD, Crew AP, Crews CM, Coleman KG. Proc. Natl. Acad. Sci. U. S. A. 2016; 113: 7124
15b Hu J, Hu B, Wang M, Xu F, Miao B, Yang C.-Y, Wang M, Liu Z, Hayes DF, Chinnaswamy K, Delproposto J, Stuckey J, Wang S. J. Med. Chem. 2019; 62: 1420
15c Wei J, Hu J, Wang L, Xie L, Jin MS, Chen X, Liu J, Jin J. J. Med. Chem. 2019; 62: 10897

16 Yamazaki Y, Kohno K, Yasui H, Kiso Y, Akamatsu M, Nicholson B, Deyanat-Yazdi G, Neuteboom S, Potts B, Lloyd GK, Hayashi Y. ChemBioChem 2008; 9: 3074

Supplementary Material

Supporting Information (PDF)