Replacing the phthalimide core in thalidomide with benzotriazole

Mikhail Krasavin; Andrey Bubyrev; Alexander Kazantsev; Christopher Heim; Samuel Maiwald; Daniil Zhukovsky; Dmitry Dar'in; Marcus D Hartmann; Alexander Bunev

doi:10.1080/14756366.2021.2024525

Replacing the phthalimide core in thalidomide with benzotriazole

J Enzyme Inhib Med Chem. 2022 Dec;37(1):527-530. doi: 10.1080/14756366.2021.2024525.

Authors

Mikhail Krasavin¹, Andrey Bubyrev¹, Alexander Kazantsev¹, Christopher Heim², Samuel Maiwald², Daniil Zhukovsky¹, Dmitry Dar'in¹, Marcus D Hartmann², Alexander Bunev³

Affiliations

¹ Institute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russia.
² Department of Protein Evolution, Max Planck Institute for Developmental Biology, Tübingen, Germany.
³ Medicinal Chemistry Center, Togliatti State University, Togliatti, Russia.

Abstract

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 CRL4A^CRBN 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.

Keywords: Cereblon; benzotriazole; carbene N-H insertion; diazo compounds; immunomodulatory drugs; phthalimide.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Structure
Structure-Activity Relationship
Triazoles / chemical synthesis
Triazoles / chemistry
Triazoles / pharmacology*
Ubiquitin-Protein Ligases / antagonists & inhibitors*
Ubiquitin-Protein Ligases / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Triazoles
benzotriazole
Ubiquitin-Protein Ligases

Grants and funding

This research was supported by the Russian Foundation for Basic Research (project grant 19–33-90016) and institutional funds of the Max Planck Society.