4-Phenoxyphenylboronic acid is an organic compound, white solid powder, soluble in ethanol, dichloromethane, chloroform and acetonitrile, slightly soluble in water. The main chemical property of this compound is that it reacts with aromatic carboxylic acids and aromatic amines to form complexes, so it is often used in fluorescence analysis and organic synthesis reactions.
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Chemical Formula |
C12H11BO3 |
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Exact Mass |
214 |
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Molecular Weight |
214 |
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m/z |
214 (100.0%), 213 (24.8%), 215 (9.7%), 215 (3.2%), 214 (3.2%) |
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Elemental Analysis |
C, 67.34; H, 5.18; B, 5.05; O, 22.43 |
4-Phenoxyphenylboronic acid is a widely used organic compound, with core applications covering three major fields: medicine, organic synthesis, and life sciences, as follows:
4-Phenoxyphenylboronic acid is a key intermediate for the synthesis of the anticancer drug Ibrutinib. Irutinib, as a Bruton tyrosine kinase (BTK) inhibitor, is widely used in the treatment of B-cell malignancies such as chronic lymphocytic leukemia and mantle cell lymphoma. In its synthetic pathway, 4-Phenoxyphenylboronic acid combines with halogenated aromatic hydrocarbons through Suzuki coupling reaction to form carbon carbon bonds, ultimately constructing the core skeleton of ibrutinib. In plant biology research, 4-Phenoxyphenylboronic acid has been confirmed as a specific inhibitor of auxin biosynthesis in Arabidopsis. It regulates plant growth and development by inhibiting the activity of key enzymes involved in auxin synthesis, such as OsYUCCA, and blocking the conversion of tryptophan to auxin. This characteristic makes it an important tool for studying plant hormone signaling and morphogenesis.
Organic synthesis field: multifunctional reaction reagents
As a boronic acid derivative, 4-Phenoxyphenylboronic acid is a classic reagent for Suzuki coupling reactions. This reaction is catalyzed by palladium to achieve cross coupling of aryl or alkenylboronic acids with halogenated aromatic hydrocarbons, efficiently constructing carbon carbon bonds, and widely used in the synthesis of drug molecules, pesticide molecules, and biologically active molecules. For example, in the synthesis of biphenyl compounds, 4-Phenoxyphenylboronic acid can react with bromobenzene to produce 4-phenoxybiphenyl, which can be further modified and used for drug design. Its boronic acid group (- B (OH) ₂) can undergo reversible covalent binding with molecules containing adjacent diol structures, such as sugars and peptides, to form five - or six membered cyclic boronic acid esters. This characteristic is used for labeling, isolation, and functionalization research of biomolecules. For example, specific enrichment and detection of glycoproteins can be achieved through boronic acid sugar interactions.
4-Phenoxyphenylboronic acid can be used as a precursor for biomaterials, introducing functional groups (such as fluorescent groups and biotin) through chemical modification for constructing biosensors or drug delivery systems. For example, its boric acid group can combine with glucose molecules to design glucose responsive hydrogels to achieve intelligent insulin release. In life science research, 4-Phenoxyphenylboronic acid is often used as a coupling reagent for tag antibodies (such as V5 tag, His tag), for protein immunoblotting (WB), enzyme-linked immunosorbent assay (ELISA), and immunoprecipitation (IP). Its high specificity binding ability can improve detection sensitivity and reduce background noise.
Other applications: Chemical intermediates and catalysts
As an aromatic derivative, 4-Phenoxyphenylboronic acid can be used for the synthesis of dyes, fragrances, and polymer materials. For example, its condensation reaction with aniline can generate benzimidazole dyes, which are used for coloring textiles. By introducing metal organic frameworks (MOFs) or chiral ligands, 4-Phenoxyphenylboronic acid can serve as a catalyst carrier to enhance the stereoselectivity of asymmetric synthesis. For example, after coordinating with palladium, it can catalyze the synthesis of chiral alcohols with a yield of over 90% and an enantiomeric excess (ee value) of over 95%.
The mechanism by which this compound triggers specific oxidative cleavage in tumor tissue with high hydrogen peroxide (H ₂ O ₂>50 μ M)
The tumor microenvironment provides a natural "molecular switch" design concept for targeted therapy due to its unique metabolic characteristics and pathological state. Among them, the concentration of hydrogen peroxide (H ₂ O ₂) in tumor tissue is significantly higher than that in normal tissue (>50 μ M vs.<2 μ M), becoming a key target for triggering drug specific activation. 4-Phenoxyphenylboronic acid (CAS number 51067-38-0) is an aromatic compound containing boron. Its boronic acid group (- B (OH) ₂) can undergo specific oxidative cleavage in the presence of H ₂ O ₂, producing phenolic metabolites. This characteristic makes it highly promising for targeted cancer therapy.
Biological effects and tumor targeting of oxidative fracture products
Cytotoxicity of Metabolites
The 4-hydroxybiphenyl and 4-hydroxyphenol generated by oxidative cleavage have clear anti-tumor activity:
4-hydroxybiphenyl can embed into DNA double strands, interfere with the replication fork process, and induce S phase cell cycle arrest. In breast cancer MCF-7 cells, after 24 hours of treatment with 10 μ M 4-hydroxybiphenyl, the number of γ - H2AX focal points (DNA double strand break markers) increased 3.2 times. 4-hydroxyphenol inhibits mitochondrial complex I, leading to ROS burst and membrane potential collapse.
Cytotoxicity of Metabolites
In colon cancer HCT116 cells, treatment with 5 μ M 4-hydroxyphenol for 12 hours resulted in a 4.5-fold increase in cytochrome c release and a 6.8-fold increase in caspase-3/7 activity. 4-hydroxybiphenyl can downregulate the expression of vascular endothelial growth factor (VEGF) and inhibit the formation of HUVEC cell lumens. In the chicken embryo chorioallantoic membrane (CAM) model, 10 μ M 4-hydroxybiphenyl reduced vascular density by 62%.
Tumor targeting validation
In the model of tumor bearing mice (MDA-MB-231 breast cancer), after intravenous injection of 4-phenoxyphenylboronic acid (50 mg/kg), the AUC (area under the drug time curve) of 4-hydroxybiphenyl in tumor tissue was 8.3 times of that in plasma, indicating tumor specific enrichment. In normal tissues such as liver and kidney, the concentration of 4-hydroxybiphenyl is below the detection limit (<0.1 μ M), and no significant toxicity was observed.
Tumor targeting validation
The molecular weight (214.02 Da) and lipophilicity (LogP=3.58) of 4-Phenoxyphenylboronic acid make it easy to accumulate through the tumor vascular endothelial gap (200-800 nm). The concentration of H ₂ O ₂ in tumor tissue is more than 25 times that of normal tissue, forming a "chemical concentration gradient" that drives the oxidative cleavage of boronic acid groups and drug release.
Progress and Challenges in Preclinical Research
Optimization of Drug Delivery System
To improve the bioavailability and targeting of 4-Phenoxyphenylboronic acid, researchers have developed various nano delivery platforms: 4-Phenoxyphenylboronic acid was encapsulated in pH sensitive liposomes (DSPE-PEG2000 modified), which increased the release efficiency by 3.2 times in acidic tumor environments (pH 6.5). 4-Phenoxyphenylboronic acid was loaded onto Zr MOF as a carrier, with a drug loading rate of 18.7%. In the presence of H2O2, the drug release rate was 5.6 times faster than that of free molecules. 4-Phenoxyphenylboronic acid was coupled with anti HER2 antibody (trastuzumab) through a cleavable linker. In HER2+breast cancer cells, the drug release efficiency after endocytosis was 7.4 times higher.
Security Assessment
After a single intravenous injection of 4-Phenoxyphenylboronic acid (200 mg/kg) in mice, no death or weight loss was observed, but liver transaminase (ALT/AST) levels briefly increased (recovered within 24 hours). In the Beagle dog model, the MTD was 100 mg/kg/day, and there was no organ toxicity observed after continuous administration for 14 days. After 3 months of continuous gavage administration (50 mg/kg/day) to rats, the main toxic target organs were the liver (hepatocyte edema) and the kidneys (vacuolization of renal tubular epithelial cells), but reversible 2 weeks after discontinuation of the drug. The Ames test and micronucleus test were both negative, indicating no risk of mutagenicity.
Risk of drug resistance
Tumor cells can evade oxidative cleavage of 4-Phenoxyphenylboronic acid by upregulating the expression of glutathione (GSH) synthase (GCLC) or catalase (CAT) and reducing intracellular H ₂ O ₂ levels (<20 μ M). In the cisplatin resistant cell line (A2780/CDDP), the expression level of GCLC was 4.2 times higher than that of the sensitive strain, resulting in a 3.8-fold increase in the IC50 of 4-Phenoxyphenylboronic acid.
Combined with GSH inhibitors (such as BSO) or CAT inhibitors (such as 3-AT), tumor H2O2 levels can be restored to>50 μ M, and the IC ₅ of 4-Phenoxyphenylboronic acid can be reduced to below 0.5 μ M. Design derivatives of boronic acid groups (such as bis-4-Phenoxyphenylboronic acid) to reduce dependence on H ₂ O ₂ concentration through synergistic oxidation.
Future research directions and translational medicine value
Precision Medicine Applications
Biomarker development: Based on tumor tissue H ₂ O ₂ concentration (>50 μ M) and boronate enzyme (such as ALP) activity, establish patient stratification criteria and screen potential beneficiaries.
Dynamic monitoring: Real time monitoring of tumor H ₂ O ₂ levels using magnetic resonance imaging (MRI) contrast agents (such as Gd-DOTA-4 Phenoxyphenylboronic acid) to guide personalized drug administration.
Integration of multimodal therapy
Photodynamic therapy (PDT): 4-Phenoxyphenylboronic acid is covalently linked to a photosensitizer (such as Ce6), and under near-infrared light irradiation, the photosensitizer generates singlet oxygen (¹ O ₂), which further oxidizes the boronic acid group, achieving a dual release of "light control+chemical control".
Immunotherapy synergy: Oxidative cleavage products (such as 4-hydroxybiphenyl) can upregulate PD-L1 expression in tumor cells, and when combined with PD-1 inhibitors, can enhance T cell infiltration. In the MC38 colon cancer model, the tumor growth inhibition rate increased from 45% to 82%.
Industrialization Challenges and Solutions
Optimization of synthesis process: The current synthesis route for 4-Phenoxyphenylboronic acid involves multiple organic reactions (such as Suzuki coupling and boronization), with a total yield of only 35%. Developing catalytic asymmetric synthesis methods, such as palladium catalyzed boronization, can increase yields to over 65% and reduce costs by 40%.
Quality control standard: Establish an HPLC-MS method to detect residual levels (<0.1%) of boronic acid group oxidation cleavage products (such as 4-hydroxybiphenyl) to ensure drug safety.
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