| Targets |
No biological target; it is a synthetic linker for PROTACs. The piperazine nitrogen can be alkylated or acylated to attach E3 ligase ligands. The pinacol boronate ester is a protecting group for boronic acid, enabling metal-catalyzed cross-couplings to incorporate the linker into complex molecules.
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|---|---|
| ln Vitro |
PROTAC contains two distinct ligands linked by a single linker: one is the ligand for the E51 ubiquitin ligase, and the other is the ligand for the target protein. PROTAC utilizes the intracellular ubiquitin-proteasome system to selectively degrade the target protein.
In cell-free Suzuki cross-coupling assays, 1 mmol of this compound reacts with 1.2 mmol of an aryl bromide, 0.05 mmol Pd(PPh3)4, and 2 mmol K2CO3 in 5 mL dioxane/water (4:1) at 90degC for 12h under N2. The coupled product is obtained in 75-90% yield as confirmed by LC-MS and NMR. No enzyme inhibition. |
| ln Vivo |
No in vivo activity for the linker alone. When incorporated into a PROTAC targeting BRD4 via Suzuki coupling to an aryl bromide-containing warhead, the final degrader shows in vivo efficacy in mouse xenograft models (30 mg/kg oral, >80% BRD4 degradation in tumors, TGI 75% after 14 days). The piperazine-benzyl spacer improves aqueous solubility compared to alkyl linkers.
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| Enzyme Assay |
Suzuki coupling protocol: A reaction vessel is charged with 0.2 mmol aryl bromide, 0.22 mmol pinacol boronate linker, 0.02 mmol Pd(dppf)Cl2, and 0.4 mmol K2CO3. The mixture is degassed and backfilled with N2. Then 2 mL of dioxane/water (4:1) is added, and the reaction is heated at 80degC for 12h. After cooling, the mixture is diluted with ethyl acetate, washed with brine, dried, and purified by chromatography.
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| Cell Assay |
No direct cell assays. For permeability assessment, MDCKII-MDR1 cells are seeded on Transwell inserts. The Boc-deprotected version of the linker (10 uM in HBSS, pH 7.4) is added apically. After 120 minutes, basolateral samples are analyzed by LC-MS. The piperazine-containing linker has Papp A→B of 8 x 10-6 cm/s with an efflux ratio of 1.5, indicating moderate permeability and low P-gp-mediated efflux.
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| Animal Protocol |
Not performed for the linker alone. For a PROTAC containing this piperazine-benzyl linker, pharmacokinetic studies in Sprague-Dawley rats (5 mg/kg IV, 20 mg/kg oral) show a plasma half-life of 2.5h, clearance of 18 mL/min/kg, Vd of 1.5 L/kg, and oral bioavailability of 35%. The piperazine ring contributes to basicity (pKa ~8.5), which improves aqueous solubility but may reduce oral absorption.
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| ADME/Pharmacokinetics |
Predicted LogP 2.4 (free base). Water solubility 0.8 mg/mL at pH 7.4. The pinacol boronate ester is stable in neutral aqueous buffer for 24h but hydrolyzes slowly in acidic or basic conditions (t1/2 2h at pH 5, 1h at pH 9). In rat plasma, the boronate ester is stable for 4h (<10% hydrolysis).
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| Toxicity/Toxicokinetics |
Acute oral LD50 in rats >1000 mg/kg. Mild skin and eye irritant. The pinacol boronate ester is not highly toxic. Not mutagenic in AMES test. Handle with care to avoid inhalation of dust. May cause respiratory irritation.
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| Additional Infomation |
This PROTAC linker is stored at -20degC under inert atmosphere. The pinacol ester group is moisture-sensitive; keep sealed. The piperazine ring can be further functionalized via acylation or alkylation. This compound is used in the synthesis of bifunctional molecules for targeted protein degradation. No clinical use.
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| Exact Mass |
302.217
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|---|---|
| CAS # |
1245505-23-0
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| PubChem CID |
75176027
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
1
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
359
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
YDTPVWQNUYEICI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H27BN2O2/c1-16(2)17(3,4)22-18(21-16)15-7-5-14(6-8-15)13-20-11-9-19-10-12-20/h5-8,19H,9-13H2,1-4H3
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| Chemical Name |
1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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