| Title | Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars |
|---|---|
| Authors | PINGITORE, VALERIA, Martinez-Bailen, Macarena , Carmona, Ana T. , Meszaros, Zuzana , Kulik, Natalia , Slamova, Kristyna , Kren, Vladimir , Bojarova, Pavla , Robina, Inmaculada , Moreno-Vargas, Antonio J. |
| External publication | Si |
| Means | Bioorganic Chem. |
| Scope | Article |
| Nature | Científica |
| JCR Quartile | 1 |
| SJR Quartile | 1 |
| JCR Impact | 5.1 |
| SJR Impact | 0.763 |
| Publication date | 01/03/2022 |
| ISI | 000820618400004 |
| DOI | 10.1016/j.bioorg.2022.105650 |
| Abstract | Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of beta-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal beta-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic beta-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 x 10(4) times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A. |
| Keywords | Iminosugars; Click reaction; Glycosidase inhibitors; Hexosaminidases; Multivalency; In situ screening |
| Universidad Loyola members |