Rapid discovery of potent α-fucosidase inhibitors by in situ screening of a library of (pyrrolidin-2-yl)triazoles

Abstract

The synthesis of a small library of (pyrrolidin-2-yl)triazoles via copper catalysed cycloaddition of an alkynyl iminocyclopentitol and a set of commercial and synthetic azides has been achieved. The in situ screening for the activity towards α-fucosidase of the resulting triazoles has allowed the identification of one of the most potent and selective pyrrolidine derived inhibitors of this enzyme (Ki = 4 nM).

Multivalent Pyrrolidine Iminosugars: Synthesis and Biological Relevance

“…Triazole-benzyl bridged iminosugar 17 showed excellent enzyme inhibition to AFU (IC 50 = 74 nM, K i = 3.7 nM, Table 1 ) while dimer 13 (IC 50 = 1.2 μM, Table 1 ) indicated the existence of multivalency compared with its control 19b (IC 50 = 13 μM, Figure 4 ), a 10.8-fold potency enhancement. The result that compound 17 exhibited excellent inhibition toward AFU was consistent with the fact that the presence of an additional aromatic or heteroaromatic binding component close to the five membered iminocyclitols notably increases their inhibitory activity to AFU, which was shown by Robina [ 83 ], Behr [ 125 ], and Wong [ 126 ]. To further explore the ligand-enzyme binding modes, stereoisomeric pyrrolidine dimers ( 33 , ent -33 , and meso -33 , Figure 5 ) with short and flexible space were synthesized [ 84 ].…”

“…The synthesis of the divalent iminosugars 14 and 15 was started from the known compound 28 [ 83 ], which was reacted with benzylamine and sodium triacetoxyborohydride, followed by acidification and deprotection to afford compound 15a in 26% yield. Dimer 15b was obtained by debenzylation of 15a under the H 2 /Pd/C system in 65% yield.…”

“…For exploration, the amino-protected dimer 29 and trimer 30 were both deprotected under hydrochloric acid to generate the target products 14 and 31 , which were likewise tested towards α-fucosidase. Dimer 17 was synthesized due to the good inhibitory activities of (pyrrolidin-2-yl)triazoles shown by the researchers previously [ 83 ]. Thus, after the reduction of 28 to 32 , target dimer 17 was generated through a two-step reaction by treating excess 32 with 1,3-bis(azidomethyl)benzene under the catalysts of CuI and DIPEA, followed by acidification.…”

“…Alkynyl pyrrolidines 47 – 49 were selected as the skeletons because their analogs (pyrrolidin-2-yl)triazole and (pyrrolidin-2-yl)furans were previously shown to exhibit significant glycosidase inhibition to α-fucosidases and β-galactosidases by the same group [ 83 , 92 ]. The initial step was to prepare the different tethered alkynyl pyrrolidine derivatives 47 – 49 .…”

A second-generation ferrocene–iminosugar hybrid with improved fucosidase binding properties

“…To improve these binding potencies, the insertion of a hydrophobic substituent at position C-2 of the pyrrolidine moiety was recently attempted with success. [13][14][15] A triazole linker between the pyrrolidine and the hydrophobic aglycon permitted to optimize interactions, affording dissociation constants in the nanomolar range (Fig 1 , compound 2). With this in mind, we designed the new pyrrolidine-ferrocene conjugate 3 which features a triazole linker between the pyrrolidine and the ferrocene motifs.…”