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

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

Publication History

Received: 30 October 2023

Accepted after revision: 04 December 2023

Accepted Manuscript online:
04 December 2023

Article published online:
15 January 2024

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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.