Name: Thalidomide, propargyl
Brand: BOC Sciences
Price: 1099 USD
Availability: MadeToOrder

Purity

≥98%

ShelfLife

2 years

Storage

-20°C

Synonyms

2-(2,6-Dioxo-3-piperidinyl)-4-(2-propyn-1-yloxy)-1H-isoindole-1,3(2H)-dione

InChI Key

NOGQTNDSZFYNTM-UHFFFAOYSA-N

InChI

InChI=1S/C16H12N2O5/c1-2-8-23-11-5-3-4-9-13(11)16(22)18(15(9)21)10-6-7-12(19)17-14(10)20/h1,3-5,10H,6-8H2,(H,17,19,20)

SMILES

C#CCOC1=CC=CC2=C1C(=O)N(C2=O)C3CCC(=O)NC3=O

Background Introduction

Thalidomide, propargyl is a specialized E3 ligase ligand-linker conjugate designed for the development of targeted protein degradation tools such as PROTACs (Proteolysis Targeting Chimeras). Thalidomide is a well-characterized ligand for the cereblon (CRBN) E3 ubiquitin ligase, and the inclusion of the propargyl group provides a functional handle for further conjugation via click chemistry. This combination enables efficient and modular assembly of PROTAC molecules, which have emerged as innovative therapeutics for the selective degradation of disease-associated proteins.

Mechanism

Thalidomide, propargyl operates by harnessing the ubiquitin-proteasome system for targeted protein degradation. Upon incorporation within a PROTAC molecule, thalidomide binds to the CRBN E3 ligase complex, while the propargyl group serves as an attachment point for conjugating various pharmacophores or targeting ligands through click reactions. When the PROTAC brings the E3 ligase and the target protein into proximity, it facilitates the transfer of ubiquitin molecules to the target protein, marking it for degradation by the proteasome. This mechanism enables selective protein knockdown within cells, surpassing traditional inhibition-based strategies.

Applications

Thalidomide, propargyl is primarily used in the synthesis of cereblon-based PROTACs and molecular glues. Its versatile propargyl functional group allows for rapid and customizable conjugation with different targeting ligands or small molecules, accelerating PROTAC development and screening. Key applications include drug discovery research, the study of protein function via induced degradation, and the creation of potential therapeutics for cancer, neurodegenerative disorders, and other diseases where aberrant proteins play a critical role. Additionally, this conjugate is valuable for academic and pharmaceutical laboratories aiming to explore and expand targeted protein degradation technologies.

• Propargyl group enables versatile click chemistry conjugation for efficient PROTAC assembly
• Thalidomide-based structure ensures high-affinity CRBN E3 ligase recruitment in targeted protein degradation

1. Novel agents in development for peripheral T-cell lymphoma

Owen A O'Connor Semin Hematol . 2010 Apr;47 Suppl 1:S11-4. doi: 10.1053/j.seminhematol.2010.01.014.

Though peripheral T-cell lymphoma (PTCL) is an area of significant unmet therapeutic need, a number of new treatment options are available for patients, especially those with relapsed or refractory disease. A plethora of drugs are now in development for PTCL, but drugs that truly target novel disease biology are noticeably absent. Combinations of T-cell centric agents could produce novel platforms of therapy to replace the relatively ineffective CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimens. Among agents with T-cell activity are the folate analog pralatrexate, histone deacetylase inhibitors (HDACi) like romidepsin, the proteasome inhibitor bortezomib, the immunomodulatory agent lenalidomide, the purine nucleoside phosphorylase (PNP) inhibitor forodesine, the nucleoside analog gemcitabine, and BH3-only mimetics like ABT-263 and ABT-737.

2. Construction of sulfur-containing N-vinylimides: N-addition of imides to propargyl sulfonium salts

Yan-Jiao Wang, Jun-Wen Wang, Guo-Mei Gong, Le-Mei Wang, Jin-Yan Liang, Shou-Jie Shen RSC Adv . 2022 Apr 26;12(20):12663-12671. doi: 10.1039/d2ra01117d.

AnN-addition reaction between imides and propargyl sulfonium salts was developed to afford sulfur-containingN-vinylimides with moderate to excellent yields. Under the activation of NaOAc·3H2O, imides could undergo deprotonation and propargyl sulfonium salts could isomerize to allenic sulfonium salts. TheN-nucleophilic attack initiates the reaction and gives the desired products. Various imides, including arylimides, aliphatic imides andN-(arylsulfonyl) alkyl acylamides, and even bioactive saccharin, thalidomide and pomalidomide could provide organosulfurN-vinylimides compounds. The simple, mild and metal-free reaction conditions, the broad scope of substrates, gram-scale synthesis and convenient transformation embody the synthetic superiority of this process.

The E3 Ligase Ligand-Linker Conjugate featuring Thalidomide and propargyl is instrumental in the development of PROTACs, offering a sophisticated approach to targeted protein degradation. This conjugate integrates a versatile linker and a specific ligand to facilitate the recruitment of E3 ligase, enhancing the selective degradation of target proteins. The following provides a detailed description of this molecule.

Linker: The linker in this molecule is characterized by its moderate length and flexible nature, allowing for optimal spatial arrangement between the E3 ligase and the target protein. It is non-cleavable, ensuring stability and sustained interaction within the cellular environment.

Ligand: The ligand component is Thalidomide, a well-established E3 ligase binder known for its glutarimide moiety, which effectively recruits cereblon (CRBN) as the E3 ligase. Its structural characteristics ensure high affinity and specificity, facilitating efficient protein degradation.

Reactive Site: The propargyl group serves as the reactive site that couples with the target protein ligand. It is suitable for click chemistry reactions, such as copper-catalyzed azide-alkyne cycloaddition, which are efficient and selective for forming stable conjugations.

Recommended Target Protein Ligand: The recommended warhead for this molecule is an azide-functionalized moiety, which can efficiently undergo click chemistry with the propargyl group. This choice enhances the specificity and efficiency of the PROTAC, enabling precise degradation of target proteins. Its application is ideal for experimental studies focused on understanding protein function and validating drug targets.

May I know the mainly application of Thalidomide, propargyl?

Certainly! Thalidomide, propargyl is a Thalidomide-based Cereblon ligand that recruits CRBN proteins. Thalidomide, propargyl can be linked to target protein ligands via linkers to form IMiD-containing PROTACs.

10/9/2018

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* Our calculator is based on the following equation:
Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂