Thalidomide-O-PEG4-Acid - ≥98% , CAS No.2353563-50-3

CAS: 2353563-50-3 Cat. No.: T595102 Formula: C₂₆H₃₃N₃O₁₂ Peso molecolare: 579.6

GRADE & PURITY ≥98%

Storage

Store at -20°C

Shipped In

Ice chest + Ice pads

Application

230

Panoramica

E3 ligase ligand-linker conjugate, Thalidomide-O-PEG4-Acid, is synthesized compound that incorporates the Thalidomide based cereblon ligand and 4-unit PEG linker used in PROTAC technology.

Specifications

Specifiche e purezza

≥98%

Condizioni di conservazione di stoccaggio

Store at -20°C

Spedito in

Ice chest + Ice pads

Questo prodotto richiede spedizione a catena fredda. I servizi di terra e altri servizi economici non sono disponibili.

Purezza

≥98%

Nomi e identificatori

• Peso molecolare: 579.6

Proprietà chimiche e fisiche

• Solubilità: Solubility in Water, DCM

Application Protocols

No vendor-validated biological assay protocols (e.g., WB, IHC, IF, FC) are associated with this small-molecule building block. Application protocols depend on the downstream conjugate being synthesized.

General laboratory workflow for assembling a CRBN-based conjugate (guidance only):

1. Stock solution: Dissolve Thalidomide-O-PEG4-Acid in dry DMF or DMSO (e.g., 50 mM). If necessary, warm gently and sonicate.
2. Activation: Pre-activate the acid to an NHS ester (EDC/NHS, 0–25°C, 1–2 h) or proceed directly with HATU/DIPEA coupling.
3. Coupling: Add the activated acid (or acid + HATU) to the amine-bearing target ligand (1.1–1.5 equiv) in DMF with DIPEA (2–3 equiv). Stir at RT for 2–16 h, monitoring by LC–MS.
4. Quench/purify: Quench residual active esters with ethanolamine or water. Purify by reverse-phase prep HPLC (water/MeCN, 0.1% FA) or by precipitation if feasible.
5. Characterization: Confirm structure by HRMS and NMR; assess purity by analytical HPLC.

If conjugating to biomolecules, carry out couplings under mild aqueous-organic conditions and remove excess small molecules by desalting or dialysis. Optimize conditions empirically for each payload.

Biological Roles

This product is intended strictly for research use. The following notes describe biochemical roles relevant to its use as a tool compound component and should not be interpreted as clinical claims.

• E3 ligase engagement: The thalidomide-derived phthalimide–glutarimide scaffold is a well-established ligand for the cereblon (CRBN) substrate receptor of the CRL4CRBN E3 ubiquitin ligase complex (literature). O-PEGylation preserves CRBN binding while providing a handle for conjugation.
• Degrader design: When coupled to a target-binding ligand via the PEG4 spacer, the resulting heterobifunctional molecule can recruit CRBN in cells (research context), enabling proximity-driven ubiquitination studies of the target protein (literature concept of targeted protein degradation).
• PEG4 role: The tetraethylene glycol spacer modulates solubility, permeability, and ternary complex geometries; its length is commonly used as a baseline in degrader SAR before exploring alternative lengths/chemotypes (literature practice).
• Selectivity considerations: The thalidomide ligand biases recruitment toward CRBN; target specificity in bifunctionals is dictated by the target warhead, linker length/orientation, and cellular context.

Note: Actual cellular behavior depends on the complete conjugate and experimental system. This intermediate alone does not possess defined biological activity in isolation beyond binding to CRBN-associated assays as a ligand fragment.

Buffer Applications

This product is a small-molecule building block rather than a buffering agent. It is not typically used to prepare pH buffer systems.

Practical notes when buffers are involved in workflows:

• During bioconjugation or labeling on biomolecules, carry out amide couplings in compatible aqueous-organic media (e.g., DMF or DMSO cosolvent with phosphate, HEPES, or bicarbonate buffers) after pre-activating to NHS ester. Maintain pH 7.5–8.5 to favor amine nucleophilicity while minimizing imide hydrolysis (general guidance).
• Avoid high concentrations of primary amines (e.g., Tris) in coupling buffers, as they compete with intended amine substrates.
• After coupling, quench excess activated ester with ethanolamine or glycine, then desalt by spin columns or dialysis as appropriate for the conjugate.

No specific buffer recipes or pH ranges apply uniquely to this item.

Green Alternatives

Synthesis and use of Thalidomide-O-PEG4-Acid can be made greener by solvent and reagent selection without compromising performance.

Greener solvent choices (general guidance):

• Replace DMF/NMP in couplings with safer polar aprotics where feasible:
  • 2-Methyltetrahydrofuran (2-MeTHF) or Cyrene can be explored for some activation chemistries; PEG solubility may limit applicability—co-solvents (EtOAc, MeCN, small % i-PrOH) can help.
  • Acetonitrile offers a balance of polarity and lower toxicity vs DMF; often suitable for NHS ester formations and analytical work.
• Workup: Favor aqueous extractions with minimal chlorinated solvent use; exploit pH-switch precipitation of the carboxylate/acid to reduce solvent volumes.

Reagent alternatives and process considerations:

• Coupling reagents: COMU or T3P can reduce urea waste relative to DCC; T3P in EtOAc/2-MeTHF is a greener platform compared with DMF/HATU in some cases.
• Avoid excess reagents: Use in situ activation (EDC/NHS) with slight stoichiometric excess to minimize waste.
• Energy: Conduct at ambient temperature when possible; brief gentle warming instead of prolonged reflux.
• Purification: Consider crystallization/precipitation from aqueous-organic mixtures rather than silica chromatography; for PEGylated compounds, reverse-phase prep HPLC using greener eluents (water/MeCN) is effective.

Trade-offs:

• PEG solubility often necessitates DMF or DMSO; greener replacements may demand longer times or give lower conversions. Validate substitutions on small scale before scale-up.

Pharmaceutical Uses

This material is supplied strictly for research and laboratory use. No clinical, diagnostic, or therapeutic applications are expressed or implied.

Formulation and process roles in a research/manufacturing context (general):

• Intermediate for discovery chemistry: Serves as a modular CRBN-ligand building block for assembling screening libraries of heterobifunctional molecules (e.g., degraders, molecular glues) in medicinal chemistry research.
• Conjugation handle: The terminal carboxylic acid enables formation of amide bonds to amine-containing payloads, linkers, or solid supports for resin-bound synthesis or parallel library production.
• Analytical standards: Can be used to benchmark retention times and MS responses of PEGylated CRBN ligands in method development.

Regulatory/pharmacopeia status: Not a pharmacopeial excipient or API. Any GMP-relevant specifications, impurity profiles, or residual solvent limits are not provided and would require separate qualification. For this catalog item, grade/purity and release tests are Not specified for this item; refer to CoA/Spec Sheet.

Note: If translation into process development is contemplated, establish in-house specifications (identity, purity, water, residual reagents), and qualify suppliers per quality system requirements.

Physical Properties

Item-specific physicochemical constants are not provided in the Product Data and should be confirmed on the CoA/Spec Sheet.

• Appearance: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Melting point / boiling point: Not specified for this item; refer to CoA/Spec Sheet.
• Density, refractive index: Not applicable to solids or not specified.

General/literature characteristics for O-PEGylated thalidomide acids (guidance, not specifications):

• Physical state: Typically off-white to white solid; PEGylated imide derivatives are often amorphous and may be hygroscopic.
• Solubility profile: Good solubility in polar aprotic solvents (DMSO, DMF, NMP); limited solubility in nonpolar solvents (hexanes, toluene). Aqueous solubility can improve at basic pH due to carboxylate formation; neutral water solubility is usually low to moderate.
• pKa (carboxylic acid, literature expectation): ~4–5 typical for aliphatic carboxylic acids on PEG spacers; exact value depends on substitution and should be experimentally verified.
• LogP: PEGylation substantially reduces lipophilicity relative to thalidomide; expect overall polar character (literature qualitative assessment).

Handling notes (physical): Minimize moisture uptake to maintain accurate mass during weighing; allow vial to equilibrate to room temperature before opening to avoid condensation.

Quality and Grades

Item-specific grade/purity are not listed in the Product Data and should be verified on the CoA/Spec Sheet.

• Grade/Purity: Not specified for this item; refer to CoA/Spec Sheet.

Context and expectations for this class of product:

• Research grade building block: Typically provided at high chemical purity (often ≥95% by HPLC) suitable for medicinal chemistry, linker conjugation, and materials science research. Actual assay, chromatographic purity, and residual solvent content must be confirmed on the lot-specific CoA.
• Identity verification: For complex PEGylated ligands, vendors commonly supply HPLC traces and high-resolution MS. NMR may show broadened PEG signals; integration of PEG and aromatic regions assists identity confirmation.
• Stabilizers: None are typically required for this class; if any stabilizer or counter-ion is present (e.g., as a sodium salt), it will be explicitly stated on the CoA/spec. For this item: Not specified; refer to CoA/Spec Sheet.
• UV profile: PEG linkers reduce UV intensity; phthalimide chromophore absorbs in near-UV. Low-UV impurity specs (for HPLC-grade solvents) do not apply here unless explicitly stated.
• Trace metals, residual reagents, water content: Not specified for this item; refer to CoA/Spec Sheet. If sensitive coupling chemistry is planned, consider Karl Fischer and residual solvent checks on receipt.

Recommendation: For conjugation-sensitive workflows (PROTAC assembly, click chemistry), request CoA with HPLC assay, MS, and water content to guide handling and stoichiometry.

Reaction and Applications

This O-linked thalidomide-PEG4-carboxylic acid is a versatile E3 ligase ligand module for constructing bifunctional molecules and conjugates.

Key application families:

• PROTAC assembly: Couples via the terminal carboxylic acid to amines on target ligands to yield amide-linked degraders that recruit cereblon (CRBN).
• Targeted molecular probes: Conjugation to dyes, affinity tags, or polymers for pull-downs and imaging (research use only).
• Materials science: PEGylated imide motifs can be appended to surfaces or nanoparticles to study protein recruitment phenomena in model systems.

Practical chemistry considerations:

• Coupling chemistry: Use carbodiimide/NHS (EDC·HCl + NHS or DCC/NHS) or uronium reagents (HATU, HBTU, COMU) with base (DIPEA, NMM) in DMF/NMP at 0–25°C. Pre-activation to NHS ester can facilitate bioconjugation.
• Selectivity: The carboxylate is the intended coupling handle; the imide nitrogens are far less nucleophilic. Avoid strong basic conditions that risk imide ring opening.
• Protecting-group strategy: When coupling to multi-functional ligands, protect competing amines/alcohols to control site-selectivity.
• Stereochemistry: If used in SAR or degrader campaigns, note that CRBN engagement is typically tolerant to O-alkylation but stereochemistry at the glutarimide center can influence potency; define and track enantiomeric composition if relevant (check CoA).
• Analytics: Monitor reactions by LC–MS (ESI positive/negative). PEG4 often yields broad HPLC peaks; use gradients and volatile modifiers (e.g., 0.1% FA).

Reaction Conditions

General, literature-based guidance for coupling and derivatization (not specifications for this item):

Amide coupling to a primary amine (bifunctional assembly):

• Typical setup: 1.0 equiv acid, 1.1–1.5 equiv amine, 1.1–1.5 equiv coupling reagent; base 2.0–3.0 equiv.
• Reagents/solvents: HATU or COMU (1.1–1.5 equiv), DIPEA (2–3 equiv) in dry DMF or NMP. Alternative: EDC·HCl (1.2 equiv) + NHS (1.2–1.5 equiv) with DIPEA in DMF or MeCN.
• Temperature/time: 0–25°C, 1–16 h, monitor by LC–MS. Gentle warming (30–40°C) may accelerate sluggish reactions.
• Workup: Dilute with EtOAc, wash with aqueous NaHCO3 and brine, dry, and concentrate. For polar products, reverse-phase prep HPLC is often more effective.

NHS ester pre-activation:

• Form NHS ester using EDC·HCl/NHS in dry MeCN or DMF at 0–25°C for 1–2 h. Isolate quickly or use in situ to minimize hydrolysis.

Base and moisture considerations:

• Avoid strong bases (e.g., NaH, t-BuOK) and high heat that can compromise the imide. Maintain anhydrous conditions to limit hydrolysis of activated intermediates.

Analytical monitoring:

• LC–MS with water/MeCN (0.1% FA) gradients; PEG4-containing compounds often require extended gradients for good separation. Observe diagnostic mass increase corresponding to amide formation.

Expected outcomes:

• Literature examples of CRBN–linker amide couplings generally provide good conversions and isolable yields ranging from moderate to high; confirm on small-scale before scale-up.

Safety and Handling

Authoritative hazard data for this specific item are not provided here; consult the product SDS for definitive information.

• GHS classification, signal word, pictograms, H-statements: Not specified for this item; refer to SDS.
• General lab safety (good practice):
  • Use in a chemical fume hood. Avoid inhalation of dusts/aerosols.
  • Wear appropriate PPE: lab coat, safety glasses, and suitable gloves (e.g., nitrile). Change gloves regularly when working in DMSO/DMF.
  • Avoid contact with skin and eyes. Wash thoroughly after handling.
• Incompatibilities and stability (general guidance):
  • Carboxylic acids and imides are generally stable, but avoid strong bases at elevated temperature that can promote imide ring opening or O–alkyl ether cleavage.
  • Avoid strong oxidants and strong acids capable of hydrolysis. PEG chains can undergo oxidative degradation under harsh conditions.
• Special risks/notes:
  • Dust may be irritating to respiratory tract; minimize particulate generation.
  • PEGylated materials can be hygroscopic; keep tightly closed with desiccant.
• First-aid overview (non-exhaustive; defer to SDS):
  • Inhalation: Move to fresh air; seek medical advice if symptoms persist.
  • Skin/eye contact: Rinse with water for several minutes; remove contaminated clothing; obtain medical attention if irritation continues.
  • Ingestion: Rinse mouth; do not induce vomiting; seek medical advice.
• Waste: Collect organic solutions and contaminated disposables as hazardous chemical waste according to institutional and local regulations.

Solvent Selection

Thalidomide-O-PEG4-Acid is a polar, multifunctional building block (imide, ether-rich PEG, terminal carboxylic acid). Solvent choice should prioritize solubilizing both the PEG chain and the imide core while being compatible with coupling chemistry.

• Polarity class: Polar aprotic–favoring. The PEG chain strongly enhances solubility in DMSO, DMF, NMP, and acetonitrile (MeCN). Miscibility with water is limited but can improve at basic pH (carboxylate).
• Recommended solvents (literature/practice):
  • DMSO or DMF for stock solutions (10–50 mM typical) and amide couplings.
  • NMP as an alternative for reduced volatility and good PEG solvation.
  • MeCN for HPLC and some activation steps; add small % of DMF to aid dissolution if needed.
  • Aqueous-organic systems (e.g., MeCN/water with 0.1% formic acid) for analytical HPLC.
• Less suitable: Nonpolar hydrocarbons (hexanes, heptane) and chlorinated solvents (DCM) often dissolve PEGylated acids poorly; DCM/DMF mixtures can be used if needed.
• Practical tips:
  • Warm gently (30–40°C) and sonicate to aid dissolution. Avoid prolonged heating in base.
  • For aqueous workup, adjust pH: dissolve as sodium/potassium carboxylate in basic aqueous buffer, then acidify to precipitate if isolation is desired.
  • For moisture-sensitive couplings, dry DMF/NMP and maintain low water content; PEG can carry adventitious water—pre-dry under high vacuum if necessary.

Storage and Reconstitution

Storage conditions per Product Data:

• Store at −20°C.
• Shipped in an ice chest with ice pads.

Additional handling guidance (general best practice for PEGylated small molecules; not a substitute for CoA/SDS):

• Keep container tightly sealed, protected from moisture and light. Include desiccant in secondary containment if long-term storage is planned.
• Before first use, allow vial to equilibrate to room temperature while sealed to prevent condensation.

Reconstitution:

• Preferred solvents: Dry DMSO or DMF to prepare concentrated stocks (e.g., 10–50 mM). Sonication and gentle warming (≤40°C) can help dissolution.
• Aliquoting: Prepare single-use aliquots to avoid repeated freeze–thaw cycles that can introduce moisture and degrade activated derivatives.
• Short-term storage of solutions: 2–8°C for hours to a few days in dry, inert atmosphere; assess stability by LC–MS before critical experiments.
• Long-term storage of solutions: At −20°C under inert gas in anhydrous solvent. Stability depends on matrix and purity; periodically re-qualify by HPLC/MS.

Compatibility notes:

• Avoid prolonged exposure to strong bases or acids in solution to minimize imide or PEG degradation.
• For aqueous usage, dissolve with minimal DMSO/DMF cosolvent and adjust pH as needed; prepare fresh to limit hydrolysis of any activated intermediates.

For research use only.

Structure and Identity

Thalidomide-O-PEG4-Acid is a thalidomide-derived cereblon (CRBN) ligand functionalized via the imide oxygen with a tetraethylene glycol (PEG4) spacer terminating in a carboxylic acid. This architecture is widely used as an E3 ligase–binding module for constructing heterobifunctional degraders (PROTACs) and other conjugates.

• CAS: 2353563-50-3
• Molecular formula: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.
• InChIKey: Not specified for this item; refer to CoA/Spec Sheet.

Structural features (general description):

• Core: Thalidomide contains a substituted phthalimide fused through an imide to a glutarimide; in O-linked analogs, functionalization occurs at the imide oxygen (O-alkylation), preserving the CRBN-binding pharmacophore.
• Linker: PEG4 segment (–O–CH2–CH2–O– repeated four times) imparts flexibility, polarity, and aqueous/organic compatibility.
• Terminus: Free carboxylic acid for downstream amide coupling to amines on ligands, linkers, tags, or solid supports.
• Stereochemistry: Thalidomide has a stereogenic center in the glutarimide ring in its parent form; O-PEGylation does not remove this center. Unless otherwise specified, material may be provided as racemate; confirm with CoA/Spec Sheet for this item.

2D structure (verbal): Aromatic phthalimide ring system connected via an ether to a –(CH2CH2O)4– chain ending in –CH2–CO2H; the second imide rings comprise the bicyclic imide framework typical of thalidomide.

Synthetic Utility

Functional group set and reactivity make Thalidomide-O-PEG4-Acid a high-value convergent synthon in linkerology.

Key features:

• Electrophile precursor: Carboxylic acid can be transformed to NHS esters, acid chlorides, mixed anhydrides, or activated esters (e.g., pentafluorophenyl, 4-NO2-Ph) for rapid amide formation with amines on ligands or solid supports.
• Orthogonality: The imide nitrogens of thalidomide are weakly nucleophilic/acidic and typically inert under standard amide-coupling conditions, preserving CRBN-binding motif integrity.
• PEG4 spacer: Enhances solubility in polar media, reduces aggregation, and provides spatial separation to optimize ternary complex formation in bifunctionals (literature rationale).

Common transformations (literature/general):

• Amide bond formation: HATU/DIPEA in DMF; EDC/NHS in DMF or MeCN; T3P in EtOAc/2-MeTHF for greener processes.
• Ester formation: With alcohol-bearing payloads via DCC/DMAP or Steglich conditions when an amide is not desired; note potential hydrolytic lability of esters in biology.
• Click-ready handles: Convert acid to azide- or alkyne-terminated linkers via short spacers (e.g., amide to propargylamine) for CuAAC/Sonogashira-enabled diversification.
• Solid-phase attachment: Immobilize via amide bond to amine-functional resins for parallel synthesis of linker-length SAR libraries.

Analytical support: Characterize by HRMS, 1H/13C NMR (PEG broad multiplets), and HPLC (C18, water/MeCN, 0.1% FA).

Target Specificity

This listing is a small-molecule building block and not a biologic or antibody product. Therefore, antigen/epitope specificity, clone, isotype, and species reactivity are not applicable.

Contextual note (literature): As a thalidomide-derived ligand fragment, conjugates incorporating this moiety typically recruit the cereblon (CRBN) E3 ligase. However, any target specificity in a final bifunctional construct is determined by the partnered target-binding ligand and overall molecular design, not by this intermediate alone.