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DOI: 10.1055/s-2004-817778
Parallel Solid Phase Synthesis of Tricomponent Bisubstrate Analogues as Potential Fucosyltransferase Inhibitors
Publication History
Publication Date:
10 February 2004 (online)
Abstract
A combinatorial library of 32 tricomponent bisubstrate fucosyltransferase analogs has been generated using solid-phase peptide synthesis with orthogonally protected lysine as a scaffold.
Key words
nucleosides - solid-phase synthesis - glycopeptides - combinatorial chemistry - substrate analogs
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References
Earlier (see ref. [5] ) we called these compounds ‘trisubstrate analogues’, as opposed to the bisubstrate analogues earlier reported by Hindsgaul and coworkers (see ref. [4a] ). Later on similar compounds were termed ‘tricomponent bisubstrate analogues’ on the basis that glycosyltransferases employ two, instead of three, substrates (see also ref. [4e] ).
15Compound Ia: 1H NMR (600 MHz, D2O): δ = 7.89 (s 1 H), 5.84 (d, 1 H, J = 5.5 Hz), 4.51 (d, 1 H, J = 8.4 Hz), 4.37-4.20 (m, 8 H), 3.97 (AB, 2 H), 3.87 (d, 1 H, J = 12 Hz), 3.72 (m, 4 H), 3.62-3.52 (m, 5 H), 3.43 (m, 2 H), 3.08 (br m, 2 H), 2.01 (s, 3 H), 1.61 (br m, 2 H), 1.40 (br m, 2 H), 1.25 (br m, 2 H), 1.21 (d, 3 H, J = 6.2 Hz). ESI-MS: 933.5 [M + H+]. Compound IVb: 1H NMR (600 MHz, D2O): δ = 7.87 (s 1 H), 5.84 (d, 1 H, J = 5.6 Hz), 4.51 (d, 1 H, J = 8.4 Hz), 4.28-4.12 (m, 5 H), 3.86 (d, 1 H, J = 11.5 Hz), 3.76-3.70 (m, 4 H), 3.63 (m, 4 H), 3.53 (m, 2 H), 3.43 (m, 2 H), 3.08 (br t, 2 H), 2.00 (s, 3 H), 1.65 (br m, 2 H), 1.41 (br. m, 2 H), 1.21 (br. m, 2 H), 1.14 (d, 3 H, J = 6.4 Hz). ESI-MS: 846.6 [M + H+]. Compound Va: 1H NMR (600 MHz, D2O) δ = 7.89 (s, 1 H), 5.84 (d, 1 H, J = 5.6 Hz), 4.54 (d, 1 H, J = 8.4 Hz), 4.34 (m, 2 H), 4.26 (m, 2 H), 4.18 (m, 4 H), 3.96 (m, 2 H), 3.86 (m, 1 H), 3.73 (m, 4 H), 3.62 (m, 2 H), 3.53 (m, 3 H), 3.44 (m, 2 H), 3.15-3.00 (m, 2 H), 2.00 (s, 3 H), 1.61 (br m, 2 H), 1.39 (br m, 2 H), 1.25 (br m, 2 H), 1.20 (d, 3 H, J = 6.2 Hz). ESI-MS: 933.4 [M + H+]. Compound Vb: 1H NMR (600 MHz, D2O) δ = 7.89 (s, 1 H), 5.83 (d, 1 H, J = 5.6 Hz), 4.54 (d, 1 H, J = 8.4 Hz), 4.34-4.18 (m, 5 H), 3.99-3.86 (m, 3 H), 3.76-3.43 (m, 12 H), 3.11 (br m, 2 H), 1.99 (s, 3 H), 1.62 (br m, 2 H), 1.39 (br m, 2 H), 1.25 (br m, 2 H), 1.21 (d, 3 H, J = 6.2 Hz). ESI-MS: 903.4 [M + H+].
17Compound 16 (a 1:3 mixture of 2′-en-3′-O-acetates, chemical shifts are given for the major isomer): 1H NMR (200 MHz, CDCl3): δ = 7.80 (s, 1 H, H-8), 7.11 (m, 2 H, Pac), 6.81 (m, 3 H, Pac), 5.87 (d, 1 H, J 12 = 4.8 Hz, H-1′), 5.75 (dd, 1 H, J 21 = 4.8 Hz, J 23 = 5.7 Hz, H-2′), 5.49 (t, 1 H, J 32 = 5.7 Hz, H-3′), 4.58 (s, 2 H, CH2O), 4.42 (br s, 2 H, 2 NH), 4.14 (m, 1 H, H-4′), 3.46 (ABX, 2 H, H-5′), 2.42 (m, 4 H, CH2, succinyl), 1.95 (s, 3 H, acetyl). 13C NMR (50 MHz, CDCl3): δ = 173.7, 170.9, 170.4, 169.7 (C=O), 156.5, 155.2 (C6, Cq, Pac), 147.6, 146.6 (C4, C2), 138.0 (C-8), 129.2, 121.7 (Ct, Pac), 121.0 (C5), 114.2 (Ct, Pac), 86.4, 80.4, 72.5, 70.0 (C-1′, C-2′, C-3′, C-4′), 66.3 (CH2O, Pac), 50.7 (C-5′), 28.3 (CH2, succinyl), 19.9 (CH3, acetyl). ESI-MS: 607.2 [M + Na]+, negative mode: 583.2 [M - H]-, 482.9 [M - succinic anhydride - H]-.
18Protonated molecular ion of oxazoline 7 was consistently found in the ESI MS spectra of pure GlcNAc derivatives, probably due to the loss of the aglycon in the gas phase.