Systematic Strategy for the Development of Glycosyltransferase Inhibitors: Diversity-Oriented Synthesis of FUT8 Inhibitors

Yoshiyuki Manabe; Koki Hizume; Yohei Takakura; Shinji Takamatsu; Eiji Miyoshi; Yoshihiro Kamada; Ramón Hurtado-Guerrero; Koichi Fukase

doi:10.1055/a-2221-9096

Synlett, Inhaltsverzeichnis

Synlett 2024; 35(11): 1273-1278
DOI: 10.1055/a-2221-9096

cluster

Japan/Netherlands Gratama Workshop

Systematic Strategy for the Development of Glycosyltransferase Inhibitors: Diversity-Oriented Synthesis of FUT8 Inhibitors

Yoshiyuki Manabe∗

^aDepartment of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan

^bForefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan

,

Koki Hizume

^aDepartment of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan

,

Yohei Takakura

^aDepartment of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan

,

Shinji Takamatsu

^cDepartment of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan

,

Eiji Miyoshi

^cDepartment of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan

,

Yoshihiro Kamada

^dDepartment of Advanced Metabolic Hepatology, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan

,

Ramón Hurtado-Guerrero

^eInstitute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain

^fFundación ARAID, 50018, Zaragoza, Spain

^gCopenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

,

Koichi Fukase∗

^aDepartment of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan

^bForefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan

^hCenter for Advanced Modalities and DDS, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan

› Institutsangaben

Abstract

Alle Artikel dieser Rubrik

Abstract

Glycans control various biological processes, depending on their structures. Particularly, core fucose, formed by α1,6-fucosyltransferase (FUT8), has a substantial influence on multiple biological processes. In this study, we investigated the development of FUT8 inhibitors with structural elements encompassing both the glycosyl donor (GDP-fucose) and acceptor (N-glycan) of FUT8. To efficiently optimize the structure of FUT8 inhibitors, we employed a strategy involving fragmentation of the target structure, followed by a structure optimization using a diversity-oriented synthesis approach. This study proposes an efficient strategy to accelerate the structural optimization of middle molecules.

Key words

compound libraries - diversity-oriented synthesis - glycosyltransferase - enzyme inhibitor - diversity-oriented synthesis

Volltext

Referenzen

References and Notes

1a Fuster MM, Esko JD. Nat. Rev. Cancer 2005; 5: 526
1b van Kooyk Y, Rabinovich GA. Nat. Immunol. 2008; 9: 593
1c Lichtenstein RG, Rabinovich GA. Cell Death Differ. 2013; 20: 976
1d Reily C, Stewart TJ, Renfrow MB, Novak J. Nat. Rev. Nephrol. 2019; 15: 346
1e Smith BA. H, Bertozzi CR. Nat. Rev. Drug Discovery 2021; 20: 217

2 Uozumi N, Yanagidani S, Miyoshi E, Ihara Y, Sakuma T, Gao C.-X, Teshima T, Fujii S, Shiba T, Taniguchi N. J. Biol. Chem. 1996; 271: 27810
3 Takahashi M, Kuroki Y, Ohtsubo K, Taniguchi N. Carbohydr. Res. 2009; 344: 1387
4 Wang X, Inoue S, Gu J, Miyoshi E, Noda K, Li W, Mizuno-Horikawa Y, Nakano M, Asahi M, Takahashi M, Uozumi N, Ihara S, Lee SH, Ikeda Y, Yamaguchi Y, Aze Y, Tomiyama Y, Fujii J, Suzuki K, Kondo A, Shapiro SD, Lopez-Otin C, Kuwaki T, Okabe M, Honke K, Taniguchi N. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 15791

5a Shinkawa T, Nakamura K, Yamane N, Shoji-Hosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki M, Hanai N, Shitara K. J. Biol. Chem. 2003; 278: 3466
5b Shields RL, Lai J, Keck R, O’Connell LY, Hong K, Meng YG, Weikert SH. A, Presta LG. J. Biol. Chem. 2002; 277: 26733
5c Satoh M, Shitara K, Hanai N. Trends Glycosci. Glycotechnol. 2006; 18: 129
5d Niwa R, Shoji-Hosaka E, Sakurada M, Shinkawa T, Uchida K, Nakamura K, Matsushima K, Ueda R, Hanai N, Shitara K. Cancer Res. 2004; 64: 2127

6 Wang X, Gu J, Ihara H, Miyoshi E, Honke K, Taniguchi N. J. Biol. Chem. 2006; 281: 2572
7 Wang X, Fukuda T, Li W, Gao C.-x, Kondo A, Matsumoto A, Miyoshi E, Taniguchi N, Gu J. J. Biochem. 2009; 145: 643

8a Bastian K, Scott E, Elliott DJ, Munkley J. Int. J. Mol. Sci. 2021; 22: 455
8b Liao C, An J, Yi S, Tan Z, Wang H, Li H, Guan X, Liu J, Wang Q. J. Cancer 2021; 12: 4109

9 Miyoshi E, Noda K, Yamaguchi Y, Inoue S, Ikeda Y, Wang W, Ko JH, Uozumi N, Li W, Taniguchi N. Biochim. Biophys. Acta, Gen. Subj. 1999; 1473: 9

10a Moriwaki K, Noda K, Furukawa Y, Ohshima K, Uchiyama A, Nakagawa T, Taniguchi N, Daigo Y, Nakamura Y, Hayashi N, Miyoshi E. Gastroenterology 2009; 137: 188
10b Tanaka K, Moriwaki K, Yokoi S, Koyama K, Miyoshi E, Fukase K. Bioorg. Med. Chem. 2013; 21: 1074

11 Okada M, Chikuma S, Kondo T, Hibino S, Machiyama H, Yokosuka T, Nakano M, Yoshimura A. Cell Rep. 2017; 20: 1017

12a Shen N, Lin H, Wu T, Wang D, Wang W, Xie H, Zhang J, Feng Z. Kidney Int. 2013; 84: 64
12b Wang N, Deng Y, Liu A, Shen N, Wang W, Du X, Tang Q, Li S, Odeh Z, Wu T, Lin H. Sci. Rep. 2017; 7: 16914

13 Gao C, Maeno T, Ota F, Ueno M, Korekane H, Takamatsu S, Shirato K, Matsumoto A, Kobayashi S, Yoshida K, Kitazume S, Ohtsubo K, Betsuyaku T, Taniguchi N. J. Biol. Chem. 2012; 287: 16699

14a Kajimoto T, Node M. Synthesis 2009; 3179
14b Gloster TM, Vocadlo DJ. Nat. Chem. Biol. 2012; 8: 683

15a Tu Z, Lin Y.-N, Lin C.-H. Chem. Soc. Rev. 2013; 42: 4459
15b Burkart MD, Vincent SP, Düffels A, Murray BW, Ley SV, Wong C.-H. Bioorg. Med. Chem. 2000; 8: 1937
15c Murray BW, Wittmann V, Burkart MD, Hung S.-C, Wong C.-H. Biochemistry 1997; 36: 823
15d Luengo JI, Gleason JG. Tetrahedron Lett. 1992; 33: 6911
15e Norris AJ, Whitelegge JP, Strouse MJ, Faull KF, Toyokuni T. Bioorg. Med. Chem. Lett. 2004; 14: 571
15f Ichikawa Y, Lin YC, Dumas DP, Shen GJ, Garcia-Junceda E, Williams MA, Bayer R, Ketcham C, Walker LE. J. Am. Chem. Soc. 1992; 114: 9283
15g Qiao L, Murray BW, Shimazaki M, Schultz J, Wong C.-H. J. Am. Chem. Soc. 1996; 118: 7653
15h Wong C.-H, Dumas DP, Ichikawa Y, Koseki K, Danishefsky SJ, Weston BW, Lowe JB. J. Am. Chem. Soc. 1992; 114: 7321
15i Mitchell ML, Tian F, Lee LV, Wong C.-H. Angew. Chem. Int. Ed. 2002; 41: 3041
15j Carchon G, Chrétien F, Delannoy P, Verbert A, Chapleur Y. Tetrahedron Lett. 2001; 42: 8821
15k Lee LV, Mitchell ML, Huang S.-J, Fokin VV, Sharpless KB, Wong C.-H. J. Am. Chem. Soc. 2003; 125: 9588
15l Manabe Y, Kasahara S, Takakura Y, Yang X, Takamatsu S, Kamada Y, Miyoshi E, Yoshidome D, Fukase K. Bioorg. Med. Chem. 2017; 25: 2844
15m Dai Y, Hartke R, Li C, Yang Q, Liu JO, Wang L.-X. ACS Chem. Biol. 2020; 15: 2662

16a Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ, Emmerton KM, Jeffrey SC, Klussman K, Law C.-L, Sussman D, Toki BE, Westendorf L, Zeng W, Zhang X, Benjamin DR, Senter PD. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 5404
16b Rillahan CD, Antonopoulos A, Lefort CT, Sonon R, Azadi P, Ley K, Dell A, Haslam SM, Paulson JC. Nat. Chem. Biol. 2012; 8: 661
16c Kizuka Y, Nakano M, Yamaguchi Y, Nakajima K, Oka R, Sato K, Ren C.-T, Hsu T.-L, Wong C.-H, Taniguchi N. Cell Chem. Biol. 2017; 24: 1467

17 Wang M, Zhang Z, Chen M, Lv Y, Tian S, Meng F, Zhang Y, Guo X, Chen Y, Yang M, Li J, Qiu T, Xu F, Li Z, Zhang Q, Yang J, Sun J, Zhang H, Zhang H, Li H, Wang W. Cell Death Dis. 2023; 14: 495
18 8: EtONa (1.80 mg, 26.4 μmol) was added to a solution of 4 (2.52 mg, 3.30 μmol) in anhyd EtOH (150 μL) at r.t., and the mixture was stirred for 1 d at 60 °C. Anhyd THF (200 μL) and EtONa (1.90 mg, 27.9 μmol) were at r.t., and the resulting mixture was stirred for 1 d at 60 °C. Additional anhyd THF (150 μL) and EtONa (1.50 mg, 22.0 μmol) were then added at r.t., and the mixture was stirred for 1 d at 60 °C. The mixture was neutralized with DOWEX (50W×8 50–100) at r.t. and then filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in 50% TFA–CH₂Cl₂ (400 μL). The resulting mixture was stirred for 30 min at r.t., then diluted with toluene and azeotroped twice. The residue was purified by reverse-phase HPLC [Cosmosil 5C₁₈-AR-300 4.6 × 250 mm column, 2–24% MeCN–H₂O (linear gradient; 33 min) + 0.1% HCOOH, 1.0 mL/min] to give a colorless oil; yield: 0.38 mg (21%). ¹H NMR (500 MHz, CD₃OD): δ = 8.70 (s, 1 H), 4.60 (q, J = 7.1 Hz, 2 H), 4.26–4.21 (m, 3 H), 4.08 (dt, J = 10.6, 6.0 Hz, 1 H), 3.85 (dt, J = 10.6, 5.9 Hz, 1 H), 3.65–3.59 (m, 2 H), 3.48–3.39 (m, 4 H), 2.61 (t, J = 6.0 Hz, 2 H), 1.98–1.92 (m, 2 H), 1.91–1.84 (m, 2 H), 1.53–1.48 (m, 2 H), 1.46 (t, J = 7.2 Hz, 3 H), 1.25 (d, J = 6.5 Hz, 3 H). HRMS (ESI-Orbitrap): m/z [M – H + 2 Na]⁺ calcd for C₂₁H₃₃N₆Na₂O₉S: 591.1820; found: 591.1819.

19a Kötzler MP, Blank S, Bantleon FI, Spillner E, Meyer B. Biochim. Biophys. Acta. Gen. Subj. 2012; 1820: 1915
19b Kötzler MP, Blank S, Bantleon FI, Wienke M, Spillner E, Meyer B. ACS Chem. Biol. 2013; 8: 1830
19c García-García A, Ceballos-Laita L, Serna S, Artschwager R, Reichardt NC, Corzana F, Hurtado-Guerrero R. Nat. Commun. 2020; 11: 973

20a Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
20b Tornøe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057

21 21: To a solution of 12 (29.4 μg, 0.05 μmol) in DMSO (5 μL), H₂O (8 μL) and phosphate-buffered saline (10×PBS; 5 μL) were added 17.0 μL (0.05 μmol) of a solution of 15 (0.17 μmol) in H₂O (56.0 μL), 5 μL (0.05 μmol) of a solution of THPTA (4.60 μmol) in H₂O (460 μL), 5 μL (0.05 μmol) of a solution of sodium ascorbate (10.1 μmol) in H₂O (1 mL), and 5 μL (0.05 μmol) of a solution of CuSO₄ (12.5 μmol) in H₂O (1.25 mL) at r.t., and the mixture was stirred for 3 h at 37 °C. The resulting mixture was purified by reverse-phase HPLC [Cosmosil 5C₁₈-AR-300 2.0 × 150 mm column, 5–30% MeCN–H₂O (linear gradient; 50 min) + 0.1% HCOOH, flow rate 0.2 mL/min] to give a white solid; yield: 31.7 μg [28%, estimated by UV (λ = 280 nm) absorption in HPLC analysis]. HRMS (ESI-Orbitrap): m/z [M – 2 H]^2– calcd for C₈₇H₁₃₉N₁₅O₅₂S: 1128.9213; found; 1128.9220.

Zusatzmaterial

Supporting Information