Thalidomide-5-propargyl , CAS No.2226303-74-6

CAS: 2226303-74-6 Cat. No.: T1449953 Numero EC: 970-924-5 PubChem CID: 134481527

Storage

Store at 2-8°C,Argon charged

Shipped In

Wet ice

Panoramica

Thalidomide -5-propargyl is a propargyl-modified Thalidomide , that acts as a Cereblon ligand to recruit CRBN proteins. Thalidomide -5-propargyl use alkynyl group at the end to be directly used in the synthesis of triazoles in the synthesis of PROTAC molecules, and is a key intermediate in the synthesis of PROTAC molecules based on CRBN design.

Specifications

Condizioni di conservazione di stoccaggio

Store at 2-8°C,Argon charged

Spedito in

Wet ice

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

Nomi e identificatori

Sorrisi canonici

C#CCOC1=CC2=C(C=C1)C(=O)N(C2=O)C3CCC(=O)NC3=O

IUPAC Name

2-(2,6-dioxopiperidin-3-yl)-5-prop-2-ynoxyisoindole-1,3-dione

InChIKey

GDWXJPQKRQMMQW-UHFFFAOYSA-N

INCHI

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

PubChem CID

134481527

Application Protocols

No item-specific tested application protocols are provided in the Product Data. The following generalized procedures are common for research use of propargylated CRBN ligands:

• Preparation of stock solutions (general): Dissolve the compound in anhydrous DMSO to 10–50 mM under inert gas. Vortex and, if necessary, briefly sonicate. Store aliquots to avoid repeated freeze–thaw cycles.
• CuAAC conjugation to azido‑linker (general): Combine the alkyne (1.0 equiv) and azide (1.1–1.5 equiv) in t‑BuOH/H2O (or DMSO/H2O). Add CuSO4 (5 mol%) and sodium ascorbate (10 mol%); optionally include THPTA (10–20 mol%). Stir at rt until LC/MS indicates completion, quench with EDTA, extract/purify.
• Post‑conjugation cleanup (general): Treat with copper scavenger resin as needed. Purify by silica or RP‑HPLC. Characterize by 1H/13C NMR and HRMS.

For any biological assays employing the resulting conjugates, determine working concentrations empirically and maintain DMSO ≤ recommended levels for the assay system. Always consult internal SOPs and safety documentation.

Biological Roles

This compound is intended strictly for research use; no medical or clinical uses are claimed.

• CRBN binding (literature/general for thalidomide analogs): Thalidomide derivatives act as ligands for cereblon (CRBN), the substrate receptor of the CUL4–RBX1–DDB1–CRBN E3 ubiquitin ligase complex. Binding can alter neosubstrate recruitment and ubiquitination outcomes. The 5‑substituent typically projects from the phthalimide ring into solvent, allowing linker installation with limited impact on CRBN affinity when properly configured.
• Chemical biology utility: As a propargylated CRBN recruiter, this molecule enables construction of bifunctional degraders, activity‑based probes, and pull‑down reagents by click conjugation to azide‑bearing linkers/warheads.
• Structure–function considerations:
  • The imide carbonyls and ring geometry are central to CRBN recognition; extensive modification at the glutarimide ring can diminish binding, whereas 4/5‑position substitutions on the phthalimide often retain activity (literature/general trends).
  • The terminal alkyne provides a compact handle with minimal steric bulk, aiding permeability of final constructs compared with bulkier linkers.

Any assay-dependent effects (e.g., degradation efficiency, target engagement) depend on the final conjugate design and experimental context. Verify biological activity empirically for each construct.

Buffer Applications

This item is a small-molecule building block rather than a buffering reagent. It does not form a defined conjugate acid/base pair suitable for maintaining solution pH in typical biochemical buffers.

• For assay work, prepare stock solutions in DMSO/DMF and dilute into your chosen biological buffer (e.g., PBS, HEPES) with appropriate cosolvent limits.
• If copper-catalyzed click reactions are performed in aqueous media, common buffer systems include HEPES or phosphate at near‑neutral pH, often with t‑BuOH/H2O or EtOH/H2O cosolvents and added copper/ligand (general guidance).

Green Alternatives

• Solvent choices: When performing CuAAC or coupling steps, consider greener solvents:
  • Replace DMF/NMP with 2‑MeTHF, ethyl acetate, or propylene carbonate where compatible. For aqueous‑tolerant click reactions, t‑BuOH/H2O or EtOH/H2O mixtures are effective (literature/general).
  • For chromatographic purification, favor EtOAc/hexanes or MeOH/H2O (RP) over chlorinated solvents when feasible.
• Catalyst systems: Employ ligand‑accelerated CuAAC (e.g., THPTA) to reduce copper loading, or use copper‑free SPAAC by pairing the propargyl handle with cyclooctyne‑azide strategies on the counterpart when copper must be avoided (note: requires modifying the azide partner).
• Energy efficiency: CuAAC often proceeds at ambient temperature with short reaction times, minimizing heating and energy use.
• Waste minimization: Use microscale HTE for linker SAR, apply solid‑supported copper scavengers, and quench residual metals to simplify aqueous workups.

Tradeoffs (balanced view):

• Greener solvents may reduce substrate solubility for this relatively polar aromatic imide, potentially lowering rates/yields; modest amounts of DMSO or MeCN as cosolvents can restore performance while maintaining a greener profile.

Pharmaceutical Uses

No excipient or clinical formulation role is claimed for this product. It is provided strictly for research and laboratory synthesis.

Research/manufacturing context (general):

• Synthetic intermediate: Employed as a CRBN‑ligand module in the preparation of investigational chemical probes and heterobifunctional molecules (e.g., PROTAC candidates) during discovery research.
• Affinity matrices: Can be conjugated to solid supports via CuAAC to create research‑grade affinity resins for interrogating CRBN interactions and neosubstrate recruitment in cell lysates.

Any compliance with pharmacopeial monographs (USP/EP/JP) or GMP suitability is not indicated. For regulated applications, source documentation and quality attributes must be established independently.

Physical Properties

Item-specific physicochemical specifications are not provided in the Product Data. The following notes are general/literature-oriented guidance for thalidomide analogs and should not be construed as specifications for this SKU.

• Appearance (item-specific): Not specified for this item; refer to CoA/Spec Sheet.
• Melting/boiling point (item-specific): Not specified for this item; refer to CoA/Spec Sheet.
• Density, refractive index, pKa, logP (item-specific): Not specified for this item; refer to CoA/Spec Sheet.
• Solubility (general/literature for thalidomide-like scaffolds): Frequently sparingly soluble in water and readily soluble in polar aprotic solvents such as DMSO and DMF; solubility in alcohols and chlorinated solvents can vary with substitution. The terminal alkyne generally does not dramatically increase aqueous solubility.
• UV–vis (item-specific): Not specified for this item; refer to CoA/Spec Sheet.

Practical notes (general):

• For analytical stock solutions, dry, anhydrous DMSO is commonly used (e.g., 10–50 mM), followed by dilution into assay buffers containing acceptable cosolvent levels when applicable.
• For purification, normal‑phase silica or reverse‑phase HPLC can be effective; retention increases with hydrophobic linkers if present.

Always verify item-specific values and limits on the product’s CoA/Spec Sheet.

Quality and Grades

• Grade/Purity (item-specific): Not specified for this item; refer to CoA/Spec Sheet.
• What grade implies (general): For small-molecule building blocks intended for chemical biology and library synthesis, grades typically emphasize identity (NMR/HRMS), purity by HPLC/UPLC (area %), and residual solvent/volatile profiles. Low water content and absence of inorganic salts facilitate reliable coupling reactions and clean analytical baselines.
• Stabilizers (item-specific): Not specified for this item; refer to CoA/Spec Sheet. No stabilizer is expected for this class unless noted.
• Analytical expectations (general best practice):
  • Identity confirmation by 1H/13C NMR and high-resolution mass spectrometry.
  • Purity report by HPLC with detection at multiple wavelengths (e.g., 220/254 nm) given the aromatic chromophore.
  • If chiral composition is relevant to the application, an achiral purity plus optional chiral HPLC description may be provided; most thalidomide-like CRBN ligands are used racemic unless otherwise specified.
• Documentation: For lot-specific titer/purity/ID and any residual metals/solvents, consult the CoA/Spec Sheet accompanying the shipment.

Reaction and Applications

Thalidomide‑5‑propargyl serves as a versatile CRBN-recruiting building block equipped with a terminal alkyne for modular conjugation.

Key applications (research use):

• CuAAC “click” ligation: The terminal alkyne couples efficiently with organic azides to build heterobifunctional constructs (e.g., chemical probes, affinity resins, degrader candidates). Copper(I) catalysis affords triazoles that are robust under biological assay conditions (literature/general).
• PROTAC/Degrader synthesis: Functions as the E3 ligase ligand component (CRBN binder) when connected via a suitable linker to a target‑binding warhead. The alkyne simplifies late‑stage diversification via azide‑bearing linkers.
• Surface/biomolecule modification: Attachment to azide‑functionalized beads, polymers, or biomolecules for pull‑down or enrichment studies of cereblon‑dependent interactions.
• SAR exploration: Rapid library generation by varying azido‑linker length, polarity, and geometry while keeping the CRBN anchor constant.

Practical tips (general):

• Use anhydrous, oxygen‑minimized conditions for CuAAC (e.g., CuSO4/sodium ascorbate to generate Cu(I) in situ) or preformed Cu(I) sources with stabilizing ligands (TBTA/THPTA) to limit alkyne oxidation.
• Maintain inert gas when preparing stock solutions, consistent with the recommended argon charge in storage.
• If downstream biology is anticipated, implement copper scavenging or copper‑free strain‑promoted alternatives on the azide side as needed.

Reaction Conditions

General literature guidance for common transformations of propargylated thalidomide scaffolds (not item-specific specifications):

• CuAAC (alkyne–azide click):
  • Typical solvents: t‑BuOH/H2O (1:1), EtOH/H2O, or DMSO/H2O; substrate‑dependent solubility may favor DMF or DMSO cosolvent.
  • Catalyst system: CuSO4·5H2O (1–10 mol%) with sodium ascorbate (2–20 mol%) to generate Cu(I) in situ; optional ligands (TBTA, THPTA) to accelerate and protect against oxidative alkyne degradation.
  • Temperature: 20–40°C; often complete in 0.5–4 h depending on concentrations.
  • Workup: Aqueous EDTA and copper scavengers; purification by silica gel or RP‑HPLC.
• Amide coupling (for assembling azido‑linkers or post‑click elaborations):
  • Reagents: HATU, HBTU, or EDCI/HOAt (or Oxyma/DIPEA) in dry DMF/DMF‑alternatives; 0–25°C.
  • Base: DIPEA or TEA; exclude water to prevent imide hydrolysis.
• Hydrogenation (if alkyne reduction is desired in analog synthesis):
  • Conditions: Pd/C, H2 (1 atm), MeOH/EtOAc; monitor carefully to avoid over‑reduction of sensitive motifs in the warhead/linker.

Notes:

• Maintain the product under inert atmosphere, consistent with storage guidance (argon charged).
• Avoid strong base and prolonged heating that may open the imide ring.

Safety and Handling

• GHS classification / Signal word / Pictograms / H-statements (item-specific): Not specified for this item; refer to the product SDS for authoritative hazard and precautionary statements.
• General hazards (class-level, literature): Thalidomide-class cereblon (CRBN) ligands are associated with significant reproductive and developmental toxicity in vivo. Handle as a potentially reproductive toxin and general organics irritant. Prevent skin contact, inhalation, and ingestion. Use strictly for research use only.
• Recommended PPE (good laboratory practice): Lab coat, safety glasses or splash goggles, and nitrile gloves; use double-gloving for extended handling. Employ a certified chemical fume hood when weighing, dissolving, or transferring powders/solutions.
• Engineering controls: Work in a fume hood; avoid aerosolization and dust formation. For solution prep, cap vessels and minimize open handling.
• Storage incompatibilities (general): Avoid strong oxidizers and strong bases that can promote imide ring opening. Protect from moisture and prolonged light exposure.
• Spill/accidental release (general): Avoid dust; cover with inert absorbent, collect mechanically, and dispose per institutional and regulatory guidance. Decontaminate surfaces with suitable organic solvent followed by detergent wash.
• First aid overview (general): If inhaled—move to fresh air. Skin contact—wash with soap/water. Eye contact—rinse with water for 15 minutes. Ingestion—rinse mouth; seek medical attention. Provide the SDS to responders.

Always defer to the SDS for definitive safety data and local institutional EHS protocols.

Solvent Selection

This compound is a moderately polar, aromatic imide with a terminal alkyne. It behaves as a non-ionic organic small molecule.

• Polarity class (general): Polar aprotic–compatible; hydrogen-bond acceptor but weak donor. The imide functionality increases polarity relative to simple aromatics.
• Working solvents (general guidance):
  • Strongly recommended: DMSO, DMF, NMP for stock solutions and coupling reactions.
  • Also useful: Acetonitrile, ethyl acetate, dichloromethane, THF (dependent on linker context and loading).
  • Aqueous buffers typically require a cosolvent (e.g., ≤1–2% DMSO for biophysical assays) due to limited intrinsic water solubility of thalidomide scaffolds (literature/general).
• Chromatography considerations: Aromatic chromophore enables UV detection at 220–280 nm. Reverse‑phase solvents (MeCN/H2O with 0.1% acid) are effective for analytical HPLC.
• When to choose alternatives: If aqueous compatibility is required, consider installing hydrophilic linkers on the alkyne partner or using solubilizing cosolvents/surfactants. For moisture‑sensitive couplings, use dry, degassed aprotic media.

Item-specific solubility data are not provided in the Product Data; confirm with small‑scale solubility tests in intended media.

Storage and Reconstitution

• Storage conditions (item-specific): Store at 2–8°C, argon charged (inert atmosphere), as provided. Protect from moisture and light. Minimize exposure to air during handling.
• Shipping (item-specific): Shipped on wet ice.
• Container considerations (general): Keep tightly sealed in chemically compatible vials (e.g., amber glass). For long-term storage, consider subdividing into single‑use aliquots under argon.
• Reconstitution (general guidance):
  • Solvents: Anhydrous DMSO or DMF are typical. Prepare concentrated stocks (e.g., 10–50 mM) under inert gas to limit oxidative processes.
  • Mixing: Vortex; mild warming (≤40°C) or brief sonication can assist dissolution. Filter (0.2 µm PTFE) if particulate persists.
• Freeze–thaw: Avoid repeated freeze–thaw cycles; aliquot stock solutions. If precipitation occurs upon cooling, re‑dissolve with gentle warming/agitation.
• Stability (item-specific): Not specified for this item; refer to CoA/Spec Sheet. As a general precaution, avoid prolonged exposure to basic media and strong oxidants.

Always consult the product’s CoA/Spec Sheet and SDS for lot-specific handling and stability information.

Structure and Identity

Thalidomide‑5‑propargyl is a thalidomide-derived small molecule featuring an alkyne handle for ligation chemistry.

• Core scaffold (general/literature): Thalidomide consists of a fused/linked phthalimide ring system and a glutarimide ring; it contains one stereogenic center on the glutarimide fragment (commercial thalidomide is typically racemic unless otherwise specified). In this analog, a propargyl (–CH2–C≡CH) substituent is installed at the 5‑position of the phthalimide ring, providing a terminal alkyne.
• Functional groups (general): Two imide carbonyls (bifunctional hydrogen-bond acceptors), a tertiary cyclic imide (glutarimide), and a terminal alkyne (CuAAC‑ready).
• 2D structure description (general): An aromatic phthalimide ring bearing a propargyl substituent para to one imide carbonyl, tethered via an amide-like nitrogen to a five‑membered glutarimide ring containing the single stereocenter.
• Stereochemistry (general): Unless specified otherwise, thalidomide derivatives are often provided as racemates; item-specific configuration is not specified for this product.
• CAS: 2226303-74-6
• PubChem CID: 134481527
• InChIKey: Not specified for this item; refer to CoA/Spec Sheet.
• SMILES: Not specified for this item; refer to CoA/Spec Sheet.
• Molecular formula / Molecular weight: Not specified for this item; refer to CoA/Spec Sheet.

Note: Structural identifiers (SMILES/InChIKey/formula/MW) are not provided in the Product Data and should be taken from the item’s CoA/Spec Sheet for authoritative reference.

Synthetic Utility

• Reactive handles:
  • Terminal alkyne (–C≡CH): Supports CuAAC with azides to form 1,4‑disubstituted triazoles; amenable to Glaser homocoupling (usually avoided for this application) and hydrofunctionalizations under metal catalysis (literature/general).
  • Imide nitrogen/carbonyls: Generally inert under mild conditions but can participate in selective N‑acylations or ring-opening under strong nucleophiles/bases; typically preserved during conjugation chemistry.
• Modular assembly: The propargyl group allows late‑stage diversification through click chemistry to introduce linkers of variable length/polarity without resynthesizing the CRBN anchor.
• Retrosynthetic value: Decouples the E3‑ligase ligand synthesis from the warhead/linker construction, facilitating parallel SAR and rapid library generation.
• Orthogonality: The alkyne is orthogonal to most amide couplings and to many protecting‑group manipulations, enabling convergent assembly of multifunctional constructs.
• Analytical tractability: The aromatic imide provides robust UV response; the triazole formed post‑click is stable and diagnostic in MS/NMR.

Overall, Thalidomide‑5‑propargyl is a strategically functionalized cereblon recruiter optimized for convergent, high‑fidelity conjugation workflows in chemical biology and medicinal chemistry research.

Target Specificity

This product is a small-molecule building block and not an antibody or biological macromolecule. No antigen/epitope or clone/isotype information applies.

• Item-specific targeting data are not provided. In chemical biology, thalidomide-class ligands are commonly used to engage CRBN; however, binding characteristics for this specific item must be established experimentally for each final conjugate and application.