Acid Pinacol Ester Research Articles

Enantiopure β-isocyano-boronic esters: synthesis and exploitation in isocyanide-based multicomponent reactions

Various boron-containing isocyanides have been efficiently synthesized from the corresponding enantiopure β-substituted β-amino boronic acid pinacol esters, without need for protecting group interconversion, through a two-step, purification-free procedure. They were employed in a variety of isocyanide-based multicomponent reactions, proving to be reliable components for all of them and allowing the efficient synthesis of unprecedented, boron-containing peptidomimetics and heteroatom-rich small molecules, including biologically relevant cyclic boronates. Jointing together the β-amido boronic acid moiety, deriving from the isocyanide component, with prominent pharmacophoric rings emerging from the multicomponent process, a successful application of the molecular hybridization concept could be realized.Graphical abstract

The novel boric acid modified material as micro separation plant for 1,3-BDO: Adsorption behavior and mechanism

As an important fine chemical, the research on adsorption separation of 1,3-butanediol (1,3-BDO) is still blank. In this study, the novel boric acid modified polystyrene material PS-BA-1 (boric acid content 1.169 mmol·g−1) was synthesized via introducing boric acid pinacol ester into the matrix and deprotection reaction. The adsorption capacity of PS-BA-1 for 1, 3-BDO reached 0.422 mmol·g−1 (water) and 0.947 mmol·g−1 (EtOH), while that of commercial resin CHA-111 was only 0.258 mmol·g−1 and 0.012 mmol·g−1. Interestingly, Freundlich equation could better describe the adsorption process in water (R2 ≥ 0.989) while Langmuir equation fit the EtOH system with higher correlation coefficients (R2 ≥ 0.990), respectively, indicating the adsorption process was reversible and non-ideal in water. Meanwhile, the kinetic adsorption could be better modeled by Pseudo-second-order equation (R2water = 0.991, R2EtOH = 0.990) and the k2-water (21.094*10-2) was higher than that of EtOH (3.516*10-2), demonstrating the mass transfer diffusion rate in water was faster. The breakthrough point for PS-BA-1 was 160 ∼ 162 BV in EtOH solution which was about twice of that of water system (83 ∼ 85 BV), and the column could be completely regenerated. Subsequently, PS-BA-1 was more conducive to the separation of 1,3-BDO in binary competitive experiments, indicating six-member borate esters was more stable binding structure. The computational chemistry further certified the adsorption selectivity between 1,3-BDO and PS-BA-1 as ΔG was lowest (-11.456 kcal·mol−1).

Nanophotosensitizers Composed of Phenyl Boronic Acid Pinacol Ester-Conjugated Chitosan Oligosaccharide via Thioketal Linker for Reactive Oxygen Species-Sensitive Delivery of Chlorin e6 against Oral Cancer Cells.

Chlorin E6 (Ce6)-incorporated nanophotosensitizers were fabricated for application in photodynamic therapy (PDT) of oral cancer cells. For this purpose, chitosan oligosaccharide (COS) was conjugated with hydrophobic and reactive oxygen species (ROS)-sensitive moieties, such as phenyl boronic acid pinacol ester (PBAP) via a thioketal linker (COSthPBAP). ThdCOOH was conjugated with PBAP to produce ThdCOOH-PBAP conjugates and then attached to amine groups of COS to produce a COSthPBAP copolymer. Ce6-incorporated nanophotosensitizers using the COSthPBAP copolymer were fabricated through the nanoprecipitation and dialysis methods. The Ce6-incorporated COSthPBAP nanophotosensitizers had a small diameter of less than 200 nm with a mono-modal distribution pattern. However, it became a multimodal and/or irregular distribution pattern when H2O2 was added. In a morphological observation using TEM, the nanophotosensitizers were disintegrated by the addition of H2O2, indicating that the COSthPBAP nanophotosensitizers had ROS sensitivity. In addition, the Ce6 release rate from the COSthPBAP nanophotosensitizers accelerated in the presence of H2O2. The SO generation was also higher in the nanophotosensitizers than in the free Ce6. Furthermore, the COSthPBAP nanophotosensitizers showed a higher intracellular Ce6 uptake ratio and ROS generation in all types of oral cancer cells. They efficiently inhibited the viability of oral cancer cells under light irradiation, but they did not significantly affect the viability of either normal cells or cancer cells in the absence of light irradiation. The COSthPBAP nanophotosensitizers showed a tumor-specific delivery capacity and fluorescence imaging of KB tumors in an in vivo animal tumor imaging study. We suggest that COSthPBAP nanophotosensitizers are promising candidates for the imaging and treatment of oral cancers.

Ph4P]+[Cu(CF2H)2]−: A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation

AbstractThe quest of the active species in copper‐mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4P]+[Cu(CF2H)2]−2. Complex2was able to difluoromethylate a variety of electrophiles including electron‐deficient and electron‐rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex2reacted with various lithiumnbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex2could transmetalate the difluoromethyl reagent to other metals such as [Ph4P]+[CuCl2]−and [(DPPF)PdCl2].

Ph4 P]+ [Cu(CF2 H)2 ]- : A Powerful Difluoromethylating Reagent Inspired by Mechanistic Investigation.

The quest of the active species in copper-mediated difluoromethylation of aryl halides led to the discovery of a powerful difluoromethylating reagent [Ph4 P]+ [Cu(CF2 H)2 ]- 2. Complex 2 was able to difluoromethylate a variety of electrophiles including electron-deficient and electron-rich aryl iodides, heteroaryl iodides, activated heteroaryl bromides, chloride and aryl bromides with a directing group, as well as other electrophiles such as alkenyl iodide, benzyl bromides, allyl bromides, alkyl iodide, allyl carbonates and acid chloride. In addition, in the presence of an oxidant, complex 2 reacted with various lithium nbutyl arylboronic acid pinacol esters, alkyne and heteroarene. Moreover, complex 2 could transmetalate the difluoromethyl reagent to other metals such as [Ph4 P]+ [CuCl2 ]- and [(DPPF)PdCl2 ].

A novel H2O2-activated NIR fluorescent probe for imaging β-amyloid fibrils and mitochondrial viscosity

Alzheimer's disease (AD) is an incurable chronic neurodegenerative disease. Until now, β-amyloid, mitochondrial viscosity and the relatively high concentration of hydrogen peroxide (H2O2) have been reported to be related with AD undergoing mutual interactions. In this work, a novel NIR fluorescent probe CBP was designed, synthesized and could be activated by H2O2 to release CBD, which was used to image β-amyloid fibrils in brain slices from transgenic mouse model and mitochondrial viscosity in living cells. CBP itself showed weak response towards β-amyloid and viscosity. However, upon exposure to H2O2, CBP was oxidized to the product CBD, which was accompanied with a slight fluorescence “turn-on” effect, attributing to the departure of the quenching group of the boronic acid pinacol ester. The resulting product CBP under H2O2 was highly responsive to the viscosity increase with a remarkable fluorescence enhancement at 635 nm by 53.5 folds, and simultaneously exhibited high specificity and selectivity towards Aβ1-42 aggregates with a fluorescence increase at 618 nm. Furthermore, CBP under H2O2 was applied in imaging β-amyloid fibrils in brain slices of AD transgenic mice and mitochondrial viscosity at the cellar level. Therefore, this novel NIR H2O2-activated fluorescent probe might serve as a dual imaging agent for β-amyloid fibrils and mitochondrial viscosity with low background, attributing to the H2O2-activation-induced fluorescence enhancements.

Facile synthesis of a triazine-based porous organic polymer containing thiophene units for effective loading and releasing of temozolomide

Abstract Suzuki cross-coupling reaction was employed to easily obtain a triazine-based porous organic polymer (2,4,6-tris(5-bromothiophene-2-yl)-1,3,5-triazine [TBrTh]–1,3,5-benzene-triyltriboronic acid pinacol ester [BTBPE]–covalent triazine framework [CTF]) containing thiophene units. The chemical structure of TBrTh–BTBPE–CTF was revealed by solid-state 13C NMR, Fourier-transform infrared, and X-ray photoelectron spectroscopy. TBrTh–BTBPE–CTF with an amorphous structure exhibited excellent thermal stability and intrinsic porosity (373 m2·g−1 of Brunauer–Emmett–Teller surface area). Consequently, temozolomide (TMZ) was used as an oral alkylating agent in melanoma treatment to explore the drug loading and releasing behavior of TBrTh–BTBPE–CTF as a result of the low cytotoxicity of thiophene-based polymers. The successful loading of TMZ within the polymeric structure was suggested by thermogravimetric analysis and N2 sorption isotherms. The release experiments were performed in phosphate-buffered saline at pH values of 5.5 and 7.4, exhibiting good controlled-release properties. These results suggest that the current porous organic polymer is expected to be a drug carrier for the delivery and release of TMZ.

Supramolecular Self-Assemblies with Self-Supplying H2O2 and Self-Consuming GSH Property for Amplified Chemodynamic Therapy.

Fe-based chemodynamic therapy (CDT) has become one potential method for cancer therapy due to its lower side effect and tumor-specific property. During the process of CDT, the lack of active targeting and biodegradable ability, insufficient endogenous H2O2, and overexpressed GSH in the tumor were responsible for the unsatisfactory therapeutic performance. Hence, we report host-guest interaction-based supramolecular polymers (HGSPs) that were constructed with the biomacromolecule β-cyclodextrin-grafted hyaluronic acid (HA-CD) as the active targeting host unit and hydrophobic ROS-responsive ferrocene-(phenylboronic acid pinacol ester) (Fc-BE) as the guest unit. HGSPs can further self-assemble into self-assemblies (HGSAs) and encapsulate PA as the prooxidant. After CD44-receptor-mediated cellular internalization, HGSAs could disassemble and release PA to elevate the H2O2 level for the production of higher cytotoxic hydroxyl radicals (•OH) through the Fc-induced Fenton reaction. Moreover, quinone methide (QM) was generated to downregulate antioxidant GSH. The enhancement of H2O2 and consumption of GSH were favorable for CDT due to the amplified oxidative stress. In vivo experimental results indicated that HGSAs@PA might be used as an active targeting amplified CDT agent.

A Two-Photon Fluorescent Probe for the Visual Detection of Peroxynitrite in Living Cells and Zebrafish.

Peroxynitrite (ONOO−), as an important reactive oxygen species (ROS), holds great potential to react with a variety of biologically active substances, leading to the occurrence of various diseases such as cancer and neurodegenerative diseases. In this work, we developed a novel mitochondria-localized fluorescent probe, HDBT-ONOO−, which was designed as a mitochondria-targeting two-photon fluorescence probe based on 1,8-naphthylimide fluorophore and the reactive group of 4-(bromomethyl)-benzene boronic acid pinacol ester. More importantly, the probe exhibited good biocompatibility, sensitivity, and selectivity, enabling its successful application in imaging the generation of intracellular and extracellular ONOO−. Furthermore, exogenous and endogenous ONOO− products in live zebrafish were visualized. It is greatly expected that the designed probe can serve as a useful imaging tool for clarifying the distribution and pathophysiological functions of ONOO− in cells and zebrafish.

Fluorescein Derivative Immobilized Optical Hydrogels: Fabrication and Its Application for Detection of H2O2.

A novel fluorescein-based probe FLA-Boe was developed for detecting H2O2. Modified by 2-Bromomethylphenylboronic acid pinacol ester, FLA-Boe is a Fluorescein derivative with eminent photostability and remarkable H2O2 sensitivity and selectivity. FLA-Boe was utilized to synthesize hydrogel sensors in the manner of guest–host interaction by taking advantage of its aforementioned features. The hydrogel sensor can be used to detect H2O2 effectively in both flowing and static water environments with satisfactory performance. It is expected that this application may open a new page to develop a neoteric fluorescent property analysis method aiming at H2O2 detection.

Etherification of Fluoroarenes with Alkoxyboronic Acid Pinacol Esters via C-F Bond Cleavage.

Potassium-base-mediated defluoroetherification of aryl and heteroaryl fluorides with alkoxyboronic acid pinacol esters under transition-metal-free conditions is reported. This protocol efficiently and safely provides a wide variety of aryl ethers in high yields without using metal catalysts, specific ligands, and harsh conditions to selectively forge Csp2-O bonds via the Csp2-F cleavage. This method can be applied to the late-stage etherification of structurally complex Csp2-fluorides and bioactive alcohols, such as β-estradiol, calciferol, and tocopherol.

Diethyl α-aminophosphonate containing lubricating additives synthesized from (3-aminophenyl)boronic acid pinacol ester

In this paper, (3-aminophenyl)boronic acid pinacol ester was employed as a raw material to react with different aromatic aldehydes. Then diethyl phosphite was introduced to produce the addition reaction of carbon nitrogen double bond to prepare four diethyl α-aminophosphonate derivatives, which were diethyl[phenyl({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP1), diethyl[(4-methoxyphenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP2), diethyl [(4-nitrophenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP3), and diethyl[(4-methylphenyl)({[3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino})methyl]phosphonate (BNP4). The prepared compounds were characterized by 1H and 13C NMR, MS, FT-IR and PL (Photoluminescence Spectroscopy). Four derivatives perform high thermal stability. In addition, it exhibits good friction properties for rapeseed oil (RSO) at low concentrations. Compared with BNP1, BNP2 and BNP4, BNP3 exhibits best on friction-reducing and anti-wear performances attributed to the strong electron withdrawing ability of the nitro group in BNP3, which is also reflected in the solid-state fluorescence. Therefore, the four diethyl α-aminophosphonate derivatives have potential industrial applications as lubricant additives.

Host-guest interactions based supramolecular complexes self-assemblies for amplified chemodynamic therapy with H2O2 elevation and GSH consumption properties

Although endogenous H2O2 is overexpressed in tumor tissue, the amount of endogenous H2O2 is still insufficient for chemodynamic therapy (CDT). In addition, the abundant cellular glutathione (GSH) could also consume •OH for reduced CDT. Thus, the elevation of H2O2 and the consumption of GSH in tumor tissue are essential for the increased •OH yield and amplified CDT efficacy. In this paper, host-guest interactions based supramolecular complexes self-assemblies (SCSAs) were fabricated by incorporating cinnamaldehyde (CA) and PEG-modified cyclodextrin host units (mPEG-CD-CA) with ferrocene-(phenylboronic acid pinacol ester) conjugates (Fc-BE) on the basis of CD-induced host-guest interactions. After being internalized by cancer cells, CA can be released from SCSAs through the pH-responsive acetal linkage, elevating the H2O2 level by activating NADPH oxidase. Then, Fc can catalyze the H2O2 to higher cytotoxic hydroxyl radicals (•OH). Moreover, quinone methide (QM) can be produced through H2O2-induced aryl boronic ester rearrangement and further consume the antioxidant GSH. In vitro and in vivo experiments demonstrate that SCSAs can be provided as potential amplified CDT nanoagents.

A prodrug of 3-(ferrocenylaminocarbonyloxymethyl)phenol activated by reactive oxygen species in cancer cells

Hybrid drugs containing ferrocene and phenol residues, whose π systems are not conjugated with each other, exhibit potent anticancer activity as previously reported. Few important open questions are remaining before practical application of these drugs becomes possible. First, their mode of action is not fully clarified. Second, it is not known whether these drugs exhibit cancer cell specificity. Third, due to the presence of the phenol moiety, these drugs can potentially be oxidatively deactivated and eliminated via phase II metabolism when applied in vivo. In this paper we report on synthesis of three prodrugs of aminoferrocene-phenol hybrids, where the phenolic OH group is masked as a boronic acid pinacol ester. We confirmed that the best prodrug in this small series p5 is activated in human ovarian cancer A2780 and Burkitt's lypmphoma BL-2 cells, but remains inactive in representative normal SBLF9 cells. Since p5 does not contain free phenolic OH groups, it will not be metabolized as phenols in vivo. We confirmed that the mechanism of anticancer activity of aminoferrocene-phenol prodrug p5 relies on generation of reactive oxygen species in cells.

Orthogonal C-B Bond Transformation as an Approach for Versatile Synthesis of End-Functionalized Polymers.

Conventionally inaccessible end-functionalized vinyl polymers were synthesized via orthogonal side-chain replacement for terminal and repeating units of poly(alkenyl boronate)s. A terminal-defined polymer of isopropenyl boronic acid pinacol ester (IPBpin) was synthesized via RAFT polymerization, and subsequent cobalt (Co)-catalyzed end olefination afforded the polymer carrying the C(sp2)-B bond at the terminal and the C(sp3)-B bond in repeating units. Herein, the terminal C(sp2)-B bond was selectively transformable via palladium (Pd)-catalyzed Suzuki-Miyaura cross coupling, and subsequent transformation of the repeating C(sp3)-B unit gave the poly(α-methyl vinyl alcohol) [poly(MVA)] bearing various functional groups at the terminal. The boron-based stepwise polymer reaction thus overcame the synthetic difficulty of the end-functionalized poly(MVA), which is ascribed to the poor polymerization ability of the corresponding acetate monomer, i.e., isopropenyl acetate.

19F magnetic resonance probes for detecting formaldehyde

Herein we report two separate 19F magnetic resonance (MR) probes responsive towards formaldehyde. Both agents were synthesized in a single step via aminoallylation of either 4-fluorobenzaldehyde (1FA) or 4-(trifluoromethyl)benzaldehyde (3FA) with ammonia and allylboronic acid pinacol ester. Condensation of the resulting homoallylic amines 1FA and 3FA with formaldehyde, followed by a 2-aza-Cope rearrangement and subsequent hydrolysis affords 4-fluorobenzaldehyde and 4-(trifluoromethyl)benzaldehyde, respectively. In the case of 1FA, this transformation is evidenced by a concomitant downfield shift in the 19F MR signal from −115 ppm to −103 ppm. Further, this transformation is selective towards formaldehyde over other reactive carbonyl species. While 3FA exhibits similar selectivity towards formaldehyde, this more sensitive probe is limited by the small chemical shift difference (0.7 ppm) following its activation.

Bioinspired Hydrogen Peroxide-Activated Nanochannels and Their Applications in Cancer Cell Analysis.

Bioinspired nanochannels that manipulate ion transport have shown great potential for understanding complex physiological processes. Herein, inspired by the gating function of the biological ion channels, we designed and constructed artificial hydrogen peroxide (H2O2)-activated nanochannels by decorating the inner pore surface with 4-(phenoxymethyl) benzeneboronic acid pinacol ester (PBAE). Benefiting from the specific hydrolysis reaction between H2O2 and PBAE in the confined nanochannels, the functionalized artificial nanochannels exhibited a highly selective and sensitive response toward H2O2. The system could switch between open/closed states in the presence/absence of H2O2 by the ionic current test. Meanwhile, comsol simulations were carried out to evidence the mechanism of hydrogen peroxide triggered regulation of ion transport by the nanochannels. It was found that the surface charge density of the nanochannels changed along with the addition of H2O2. Furthermore, based on the sensing strategy, the PBAE-functionalized nanochannel membrane was applied in the detection of H2O2 in the tumor microenvironment, which achieved highly selective distinguishing of cancerous cells from normal cells. This work provides a versatile method to construct bioinspired nanochannel-based platforms for detecting small reactive molecules and offers prospects for the application of disease diagnosis and prognosis.

A ratiometric and two-photon fluorescent probe for imaging hydrogen peroxide in living cells.

As an important reactive oxygen species (ROS), hydrogen peroxide plays a significant role in the life activity system, and its abnormal levels are closely related to many diseases. Developing effective fluorescent probes for detecting hydrogen peroxide is very urgent. Therefore, we constructed a probe Z that can detect hydrogen peroxide in ratio. It has naphthimide as the fluorophore and phenylboronic acid pinacol esters as the recognition group. It shows higher sensitivity, lower detection limit, higher selectivity, and broad pH applicability. Moreover, probe Z has low cytotoxicity that can be used to detect exogenous hydrogen peroxide in HeLa cells and might be a potential tool for studying hydrogen peroxide in physiological activities.

Specifically triggered dissociation based ratiometric electrochemical sensor for H2O2 measurement in food samples

A novel ratiometric strategy based electrochemical sensor was developed to quantitative assay of H2O2 in different food samples. 4-aminophenylboronic acid pinacol ester (ABAPE) dissociation was specifically triggered by H2O2 to generate electro-active 4-aminophenol (4-AP), which not only can be oxidized to indirectly indicate the concentration of H2O2, but also endowed the sensor with high selectivity. Meanwhile, a reference probe of poly(thionine) (TH) was modified with ketjen black (KB) and gold nanoparticles (AuNPs) on electrode surface. KB and AuNPs displayed high electrocatalytic activity to 4-AP. A current ratio between 4-AP and TH (i/iTH) showed a good linear relationship with the concentration of H2O2 in a range of 3.0 × 10−7 – 1.0 × 10−4 mol/L (0.010 ppm − 3.40 ppm) with a limit of detection of 2.6 × 10−7 mol/L (0.009 ppm) (S/N = 3). Moreover, the ratiometric strategy based sensor possessed good accuracy, reliability, and stability, and successfully determined H2O2 in food samples with satisfactory results.

A GSH-depleted platinum(IV) prodrug triggers ferroptotic cell death in breast cancer

Cisplatin is the first-line drug for treatment of various solid tumors including breast cancer due to the broad anti-tumor spectrum and strong anti-tumor effect. However, serious side effects and long-term medication of reduced sensitivity by high GSH in tumor cells have severely restricted its further clinical application. Herein, a GSH-depleted Pt(IV) prodrug (Platin B) based on cisplatin and 4-carboxylphenylboronic acid pinacol ester was prepared to solve the problems. As an excellent GSH scavenger, 4-carboxylphenylboronic acid pinacol ester could be activated by intracellular redox reactions to release quinone methide, thereby amplifying oxidative stress and leading to breast cancer ferroptosis therapy. Interestingly, the consumption of GSH can also reduce cisplatin inactivation, enhance the sensitivity of tumor cells to cisplatin and efficiently induce apoptosis/ferroptosis. This work highlights the use of GSH scavenger for triggering ferroptotic cell death in breast cancer. A GSH-depleted platium(IV) prodrug was successfully synthesized by oxidation and esterification reaction, which exerts an efficient tumor ferroptosis therapy.