Takeda, Kunitoshi;
Watanabe, Toru;
Smith, James R;
Vesey, David;
Tiberghien, Nathalie;
Lewis, Sian;
Powney, Ben;
... Takle, Andrew K; + view all
(2023)
Identification of novel glucocerebrosidase chaperones by unexpected skeletal rearrangement reaction.
Bioorganic & Medicinal Chemistry Letters
, 96
, Article 129531. 10.1016/j.bmcl.2023.129531.
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Abstract
Compound 5 was identified from a high-throughput screening campaign as a small molecule pharmacological chaperone of glucocerebrocidase (GCase), a lysosomal hydrolase encoded by the GBA1 gene, variants of which are associated with Gaucher disease and Parkinson's disease. Further investigations revealed that compound 5 was slowly transformed into a regio-isomeric compound (6) in PBS buffer, plausibly via a ring-opening at hemiaminal moiety accompanied by subsequent intramolecular C[sbnd]C bond formation. Utilising this unexpected skeletal rearrangement reaction, a series of compound 6 analogues was synthesized which yielded multiple potent GCase pharmacological chaperones with sub-micromolar EC50 values as exemplified by compound 38 (EC50 = 0.14 μM).
| Type: | Article |
|---|---|
| Title: | Identification of novel glucocerebrosidase chaperones by unexpected skeletal rearrangement reaction |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bmcl.2023.129531 |
| Publisher version: | https://doi.org/10.1016/j.bmcl.2023.129531 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Glucocerebrosidase; Pharmacological chaperone; Parkinson disease; Gaucher disease; Rearrangement reaction |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10183530 |
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