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
a   Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan
b   Forefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
,
Koki Hizume
a   Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan
,
Yohei Takakura
a   Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan
,
Shinji Takamatsu
c   Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
,
Eiji Miyoshi
c   Department of Molecular Biochemistry and Clinical Investigation, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
,
Yoshihiro Kamada
d   Department of Advanced Metabolic Hepatology, Graduate School of Medicine, Osaka University, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan
,
Ramón Hurtado-Guerrero
e   Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, Zaragoza, Spain
f   Fundación ARAID, 50018, Zaragoza, Spain
g   Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
,
Koichi Fukase
a   Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan
b   Forefront Research Center, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
h   Center for Advanced Modalities and DDS, Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan
› Author Affiliations
This work was financially supported by JSPS KAKENHI grants 20H05675, 20K05727, 20H04709, 21H05074, and 23K17372, as well as JST CREST grant JPMJCR20R3, AMED grants 20ek0109444h0001, 20fk0210079h0001, and JST FOREST Program grant JPMJFR211Z. R.H-G. acknowledges support from the Agencia Estatal de Investigación (PID2019-105451GB-I00 and PID2022-136362NB-I00).


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.

Supporting Information



Publication History

Received: 30 October 2023

Accepted after revision: 04 December 2023

Accepted Manuscript online:
04 December 2023

Article published online:
15 January 2024

© 2023. Thieme. All rights reserved

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  • 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.
  • 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.