Name: A 410099.1 amide-PEG2-amine-Boc
Brand: BOC Sciences
Rating: 5 (1 reviews)

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InChI Key

LEBUBVVDWZLBBX-SHHSPICZSA-N

SMILES

CN([C@@H](C)C(N[C@@H](C1CCCCC1)C(N2C[C@H](C[C@H]2C(N[C@@H]3CCCC4=CC=CC=C34)=O)NC(COCCOCCN)=O)=O)=O)C(OC(C)(C)C)=O

Pub Chem ID

146018938

Background Introduction

A 410099.1 amide-PEG2-amine-Boc is a specialized E3 ligase ligand-linker conjugate designed for use in targeted protein degradation strategies, such as the development of PROTACs (Proteolysis Targeting Chimeras). By incorporating a PEG2 (polyethylene glycol) linker and functionalized amine/Boc protecting groups, this molecule offers excellent solubility and that essential balance between flexibility and stability, driving its utility in chemical biology and drug discovery applications.

Mechanism

The mechanism of A 410099.1 amide-PEG2-amine-Boc is centered around its role as a bifunctional connector in PROTACs. The E3 ligase ligand component binds an E3 ubiquitin ligase enzyme, while the amide-PEG2-amine linker provides optimal spatial arrangement and solubility. The PEG2 linker ensures flexibility and reduces steric hindrance, whereas the Boc-protected amine allows for further functionalization or deprotection depending on synthetic needs. In a PROTAC, this conjugate facilitates the recruitment of specific proteins to the cell's ubiquitination machinery, leading to selective ubiquitination and subsequent proteasomal degradation of the target protein.

Applications

A 410099.1 amide-PEG2-amine-Boc serves as a key building block for assembling novel PROTACs and other heterobifunctional molecules aimed at targeted protein degradation. Its applications include: 1) Chemical biology research to understand protein function via rapid depletion; 2) Drug discovery—particularly the development of new therapeutics against undruggable targets; 3) Synthesis of custom bifunctional molecules for mechanistic studies or screening campaigns involving targeted degradation pathways. The flexible PEG2 linker and modifiable Boc-amine group make this conjugate highly versatile for various synthetic and biological workflows.

• Amide-PEG2 linker ensures excellent water solubility and flexibility for superior PROTAC design.
• Boc-protected amine functionality allows for easy selective deprotection and conjugation in targeted protein degradation research.

1. [Hypoglycemic sulfonylurea metabolites: clinical interest. Experiences with glibenclamide in the rat

H Samimi, L Loutan, L Balant, M Tillolès, J Fabre Schweiz Med Wochenschr. 1977 Sep 17;107(37):1291-6.

Glibenclamide, a hypoglycemic sulfonylurea, is extensively metabolized by the body and eliminated primarily in the form of its hydroxylated derivatives. The major metabolite, 4-trans-hydroxy-glibenclamide, is usually cleared rapidly from the bloodstream, but in certain pathological states (e.g. renal failure) blood levels of this product may increase. A protocol therefore was designed to test the hypoglycemic potency of this important metabolite in rats. Various quantities were injected intraperitoneally, and alterations in blood glucose concentrations were measured during a 5-hour period and compared to those in animals similarly treated with glibenclamide and in saline-injected controls. Using the dose capable of decreasing blood glucose levels by 30% (ED30) as a comparative index, it was observed that the metabolic has a marked hypoglycemic activity; though 6--7 times less potent than the parent drug, 4-trans-hydroxy-glibenclamide is nevertheless more potent than tolbutamide. Thus, while the glibenclamide metabolite probably has little influence on blood glucose when its clearance is normal, this product may exert marked effects if allowed to accumulate in the blood, as for example in renal failure. Finally, the role of such sulfonylurea metabolites should be taken into account when attempting to explain the occasional excessive and sustained hypoglycemia which occurs in some diabetic patients treated with these drugs.

A 410099.1 amide-PEG2-amine-Boc is an essential E3 Ligase Ligand-Linker Conjugate in the development of PROTACs, facilitating targeted protein degradation by linking E3 ligases to target proteins. This molecule's components, including the linker, ligand, and target protein ligand selection, are optimized for efficient and selective protein degradation.

Linker: The linker in this molecule is a PEG2 chain, providing moderate length and flexibility, which enhances solubility and facilitates optimal spatial arrangement. Its non-cleavable nature ensures stability and durability during the degradation process.

Ligand: The ligand features an amide group, which contributes to the structural stability and specificity of the conjugate. This configuration is designed to effectively bind to E3 ligases, enhancing the degradation efficiency of the target protein.

Reactive Site: The amine group serves as the reactive site, coupling with the target protein ligand through amide bond formation. This site is suitable for reactions such as amidation and carbodiimide-mediated coupling, providing robust attachment to various protein ligands.

Recommended Target Protein Ligand: A compatible warhead for this molecule is a small molecule inhibitor with a reactive carboxylic acid group. This configuration allows for efficient conjugation to the amine group, promoting selective degradation of the target protein. The application of such warheads can be pivotal in studying protein function and regulation in cellular systems.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂