Replacing the phthalimide core in thalidomide with benzotriazole

Standard

Replacing the phthalimide core in thalidomide with benzotriazole. / Krasavin, Mikhail ; Bubyrev, Andrey ; Kazantsev, Alexander; Heim, Christopher; Maiwald, Samuel; Zhukovsky, Daniil ; Dar’in, Dmitry; Hartmann, Marcus D.; Bunev, Alexander.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 37, No. 1, 31.12.2022, p. 527-530.

Research output: Contribution to journal › Article › peer-review

Author

Krasavin, Mikhail ; Bubyrev, Andrey ; Kazantsev, Alexander ; Heim, Christopher ; Maiwald, Samuel ; Zhukovsky, Daniil ; Dar’in, Dmitry ; Hartmann, Marcus D. ; Bunev, Alexander. / Replacing the phthalimide core in thalidomide with benzotriazole. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2022 ; Vol. 37, No. 1. pp. 527-530.

BibTeX

@article{b961c443e9d9497795dfb65fcc870dda,

title = "Replacing the phthalimide core in thalidomide with benzotriazole",

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 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.",

keywords = "benzotriazole, carbene N-H insertion, Cereblon, diazo compounds, immunomodulatory drugs, phthalimide, LIGAND SPACE, BINDING, MYELOMA, Humans, Apoptosis/drug effects, Structure-Activity Relationship, Cell Survival/drug effects, Antineoplastic Agents/chemical synthesis, Dose-Response Relationship, Drug, Ubiquitin-Protein Ligases/antagonists & inhibitors, Triazoles/chemical synthesis, Cell Line, Tumor, Molecular Structure, Cell Proliferation/drug effects, Enzyme Inhibitors/chemical synthesis, Drug Screening Assays, Antitumor",

author = "Mikhail Krasavin and Andrey Bubyrev and Alexander Kazantsev and Christopher Heim and Samuel Maiwald and Daniil Zhukovsky and Dmitry Dar{\textquoteright}in and Hartmann, {Marcus D.} and Alexander Bunev",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

year = "2022",

month = dec,

day = "31",

doi = "10.1080/14756366.2021.2024525",

language = "English",

volume = "37",

pages = "527--530",

journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",

issn = "1475-6366",

publisher = "Taylor & Francis",

number = "1",

}

RIS

TY - JOUR

T1 - Replacing the phthalimide core in thalidomide with benzotriazole

AU - Krasavin, Mikhail

AU - Bubyrev, Andrey

AU - Kazantsev, Alexander

AU - Heim, Christopher

AU - Maiwald, Samuel

AU - Zhukovsky, Daniil

AU - Dar’in, Dmitry

AU - Hartmann, Marcus D.

AU - Bunev, Alexander

PY - 2022/12/31

Y1 - 2022/12/31

N2 - 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.

AB - 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.

KW - benzotriazole

KW - carbene N-H insertion

KW - Cereblon

KW - diazo compounds

KW - immunomodulatory drugs

KW - phthalimide

KW - LIGAND SPACE

KW - BINDING

KW - MYELOMA

KW - Humans

KW - Apoptosis/drug effects

KW - Structure-Activity Relationship

KW - Cell Survival/drug effects

KW - Antineoplastic Agents/chemical synthesis

KW - Dose-Response Relationship, Drug

KW - Ubiquitin-Protein Ligases/antagonists & inhibitors

KW - Triazoles/chemical synthesis

KW - Cell Line, Tumor

KW - Molecular Structure

KW - Cell Proliferation/drug effects

KW - Enzyme Inhibitors/chemical synthesis

KW - Drug Screening Assays, Antitumor

UR - http://www.scopus.com/inward/record.url?scp=85125576860&partnerID=8YFLogxK

U2 - 10.1080/14756366.2021.2024525

DO - 10.1080/14756366.2021.2024525

M3 - Article

C2 - 35220840

AN - SCOPUS:85125576860

VL - 37

SP - 527

EP - 530

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

SN - 1475-6366

IS - 1

ER -

ID: 93466983