Replacing the phthalimide core in thalidomide with benzotriazole

Replacing the phthalimide core in thalidomide with benzotriazole

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate rec...

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Bibliographic Details
Main Authors: Mikhail Krasavin, Andrey Bubyrev, Alexander Kazantsev, Christopher Heim, Samuel Maiwald, Daniil Zhukovsky, Dmitry Dar’in, Marcus D. Hartmann, Alexander Bunev
Format: Article
Language:English
Published: Taylor & Francis Group 2022-12-01
Series:Journal of Enzyme Inhibition and Medicinal Chemistry
Subjects:
Cereblon
immunomodulatory drugs
phthalimide
benzotriazole
diazo compounds
carbene N-H insertion
Online Access:https://www.tandfonline.com/doi/10.1080/14756366.2021.2024525
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Summary:The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4ACRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting “benzotriazolo thalidomide” has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.
ISSN:1475-6366
1475-6374

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