Abstract

Therapeutic application of iminosugar derivatives for inhibiting sugar processing enzymes and transferases has received a lot of attention recently. From structure point of view, protonated conformation of iminosugars could mimic the transition state oxocarbenium ion, which are generated during the hydrolysis of sugar substrates by glycosidases, and exhibit inhibitory ability toward glycosidases. In this thesis, five-membered iminosugars-based scaffolds were prepared using five-membered chiral cyclic nitrones as key intermediates, followed by rapid conjugation with diverse acids through an amide coupling to generate five polyhydroxylated pyrrolidine-based libraries (5 x 127 = 635). The inhibitory ability of these libraries toward α-L-rhamnosidase were evaluated determine and the preliminary screening results showed some interesting and potent hits. After re-synthesis of these hits, the inhibitor 39 showed a Ki value of 0.24 μM against α-L-rhamnosidase with a competitive inhibition. Through the design of scaffolds and assistance of rapid diversification, and in situ bioevaluation, potent and new α-L-rhamnosidase inhibitors could be efficiently discovered. Importantly, this approach can be applied to discovery of inhibitors against various sugar processing enzymes.

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