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DOI: 10.1055/a-2221-9096
Systematic Strategy for the Development of Glycosyltransferase Inhibitors: Diversity-Oriented Synthesis of FUT8 Inhibitors
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.
Key words
compound libraries - diversity-oriented synthesis - glycosyltransferase - enzyme inhibitor - diversity-oriented synthesisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2221-9096.
- 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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- 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.