Suppressing Protodeboronation in Cu-Mediated F/F-Fluorination of Arylboronic Acids: A Mechanistically Guided Approach Towards Optimized PET Probe Development.

Fluorinated arenes play a crucial role in drug discovery, specialty materials, and medical imaging. Although several variants for Cu-mediated nucleophilic fluorination of arylboronic acids and derivatives have been developed, these protocols rarely address the occurrence and control of protodeboronation, which greatly complicates product separation and can compromise the effectiveness of a radiotracer for in vivo imaging. Consequently, simpler and more efficient procedures are needed to allow rapid F/F-fluorination of both arylboronic acids and esters while minimizing protodeboronation.

Removing Neighboring Ring Influence in Monocyclic B-OH Diazaborines: Properties and Reactivity as Phenolic Bioisosteres with Dynamic Hydroxy Exchange.

The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines.

Synergistic Nanomedicine Delivering Topoisomerase I Toxin (SN-38) and Inhibitors of Polynucleotide Kinase 3'-Phosphatase (PNKP) for Enhanced Treatment of Colorectal Cancer.

Inhibitors of a DNA repair enzyme known as polynucleotide kinase 3'-phosphatase (PNKP) are expected to show synergistic cytotoxicity in combination with topoisomerase I (TOP1) inhibitors in cancer. In this study, the synergistic cytotoxicity of a novel inhibitor of PNKP, i.e.

Divergent Synthesis of 1,2,3,4-Tetrasubstituted Cyclobutenes from a Common Scaffold: Enantioselective Desymmetrization by Dual-Catalyzed Photoredox Cross-Coupling.

Four-membered carbocycles are important structural motifs found in several natural products and drugs. Amongst those, cyclobutenes are attractive intermediates because the residual olefin can be manipulated selectively into various saturated and unsaturated analogs. Few methods exist to access chiral tri- and tetra-C-substituted cyclobutenes and they are generally limited in terms of diversification.

Expanding the Role of Boron in New Drug Chemotypes: Properties, Chemistry, Pharmaceutical Potential of Hemiboronic Naphthoids.

New chemotypes and bioisosteres can open a new chemical space in drug discovery and help meet an urgent demand for novel agents to fight infections and other diseases. With the aim of identifying new boron-containing drug chemotypes, this article details a comprehensive evaluation of the pseudoaromatic hemiboronic naphthoids, benzoxaza- and benzodiazaborines. Relevant physical properties in aqueous media (acidity, solubility, log , and stability) of prototypic members of four subclasses were determined.

Direct nucleophilic and electrophilic activation of alcohols using a unified boron-based organocatalyst scaffold.

Organocatalytic strategies for the direct activation of hydroxy-containing compounds have paled in comparison to those applicable to carbonyl compounds. To this end, boronic acids have emerged as valuable catalysts for the functionalization of hydroxy groups in a mild and selective fashion. Distinct modes of activation in boronic acid-catalyzed transformations are often accomplished by vastly different catalytic species, complicating the design of broadly applicable catalyst classes.

Unraveling the Silent Hydrolysis of Cyclic B-X/C═C Isosteres: The Striking Impact of a Single Heteroatom on the Aromatic, Acidic, and Dynamic Properties of Hemiboronic Phenanthroids.

Although heterocyclic hemiboronic acids are represented in several recently approved drugs, many questions remain unanswered regarding the physical properties and reactivity of these boranol (BOH)-containing compounds in aqueous media. Over the past 60 years, studies on the acidic and aromatic character of 10-hydroxy-10,9-boroxarophenanthrene and its boraza analog have been conflicting. In contradiction with the Lewis acidic behavior of arylboronic acids in aqueous conditions, it has been proposed that the central boroheterocyclic ring of these borophenanthroids confers sufficient aromatic character to compel the boranol unit to behave as a Brønsted acid and favor the boron oxy conjugate base, thereby avoiding the disruption of cyclic resonance that would otherwise occur with a tetravalent boronate anion.

Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis.

The disruption of polynucleotide kinase/phosphatase (PNKP) in colorectal cancer (CRC) cells deficient in phosphatase and tensin homolog (PTEN) is expected to lead to the loss of cell viability by a process known as synthetic lethality. In previous studies, we have reported on the encapsulation of a novel inhibitor of PNKP, namely, A83B4C63, in polymeric micelles and its activity in slowing the growth of PTEN-deficient CRC cells as well as subcutaneous xenografts. In this study, to enhance drug delivery and specificity to CRC tumors, the surface of polymeric micelles carrying A83B4C63 was modified with GE11, a peptide targeting epidermal growth factor receptor (EGFR) overexpressed in about 70% of CRC tumors.

Nano-Delivery of a Novel Inhibitor of Polynucleotide Kinase/Phosphatase (PNKP) for Targeted Sensitization of Colorectal Cancer to Radiation-Induced DNA Damage.

Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e.

Regiocontrolled synthesis of enantioenriched 2-substituted dehydropiperidines by stereospecific allyl-allyl cross-coupling of a chiral allylic boronate.

The palladium-catalyzed cross-coupling of an optically enriched dehydropiperidinyl boronate with cinnamyl carbonates was optimized to minimize stereochemical erosion. Although the coupling of two unsymmetrical allyl fragments may generate four possible regioisomers, the optimal procedure using (-CFCH)P as the ligand affords linear 2-allylated 3,4-dehydropiperidines exclusively (>98 : 2 rr) with enantiospecificity up to 99%.

Lewis or Brønsted? A Rectification of the Acidic and Aromatic Nature of Boranol-Containing Naphthoid Heterocycles.

Boron-containing heterocycles are important in a variety of applications from drug discovery to materials science; therefore a clear understanding of their structure and reactivity is desirable to optimize these functions. Although the boranol (B-OH) unit of boronic acids behaves as a Lewis acid to form a tetravalent trihydroxyborate conjugate base, it has been proposed that pseudoaromatic hemiboronic acids may possess sufficient aromatic character to act as Brønsted acids and form a boron oxy conjugate base, thereby avoiding the disruption of ring aromaticity that would occur with a tetravalent boronate anion. Until now no firm evidence existed to ascertain the structure of the conjugate base and the aromatic character of the boron-containing ring of hemiboronic "naphthoid" isosteres.

A synthetically lethal nanomedicine delivering novel inhibitors of polynucleotide kinase 3'-phosphatase (PNKP) for targeted therapy of PTEN-deficient colorectal cancer.

Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a major tumor-suppressor protein that is lost in up to 75% of aggressive colorectal cancers (CRC). The co-depletion of PTEN and a DNA repair protein, polynucleotide kinase 3'-phosphatase (PNKP), has been shown to lead to synthetic lethality in several cancer types including CRC. This finding inspired the development of novel PNKP inhibitors as potential new drugs against PTEN-deficient CRC.

Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct -Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning.

Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions.

Targeting Using Arylboronate/Nopoldiol Click Conjugation.

Bioorthogonal click reactions yielding stable and irreversible adducts are in high demand for applications, including in biomolecular labeling, diagnostic imaging, and drug delivery. Previously, we reported a novel bioorthogonal "click" reaction based on the coupling of ortho-acetyl arylboronates and thiosemicarbazide-functionalized nopoldiol. We now report that a detailed structural analysis of the arylboronate/nopoldiol adduct by X-ray crystallography and B NMR reveals that the bioorthogonal reactants form, unexpectedly, a tetracyclic adduct through the cyclization of the distal nitrogen into the semithiocarbazone leading to a strong B-N dative bond and two new 5-membered rings.

Diazaboryl-naphthyl-ketone: A New Scaffold with Bright Fluorescence, Aggregation-Induced Emission, and Application in the Quantitation of Trace Boronic Acids in Drug Intermediates.

This study describes the synthesis, structure, and photophysical properties of a new luminescent polyaromatic boronic acid scaffold, diazaboryl-naphthyl-ketones (DNKs). These stable compounds display extremely bright fluorescence, aggregation-induced emission, positive solvatochromism, and solid-state fluorescence. DFT calculations and X-ray crystallographic study revealed notable electronic and structural differences between these compounds and the parent diaminonaphthalene (DAN) adducts.

Design, synthesis and structure of a frustrated benzoxaborole and its applications in the complexation of amines, amino acids, and protein modification.

This study describes the design and synthesis of arylboronic acid 2, the first example of a permanently open "frustrated" benzoxaborole, along with an exploration of its application in bioconjugation. An efficient and high yielding seven-step synthesis was optimized. NMR experiments confirmed that compound 2 exists in the open ortho-hydroxyalkyl arylboronic acid structure 2-I, a form that is effectively prevented to undergo a dehydrative cyclization as a result of unfavorable geometry.

Stereodivergent Asymmetric Synthesis of α,β-Disubstituted β-Aminoalkylboronic Acid Derivatives via Group-Selective Protodeboronation Enabling Access to the Elusive Anti Isomer.

Chiral β-aminoalkylboronates generate growing interest as versatile synthetic building blocks to access β-aminoalcohols and other useful compounds, and also as bioisosteres of β-amino acids in drug discovery. In this study, the lack of methodology to access both syn and anti diastereomers of optically enriched, acyclic α,β-disubstituted β-aminoalkylboronates is addressed with the development of a divergent, diastereoselective strategy for the monoprotodeboration of β-amino -bis(boronate) precursors. To this end, new reaction conditions were successfully optimized to provide the elusive anti diastereomer by inverting a sequence of desulfinylation and protodeboronation.

Multiresponsive and Self-Healing Hydrogel via Formation of Polymer-Nanogel Interfacial Dynamic Benzoxaborole Esters at Physiological pH.

Nanocomposite hydrogels with multiresponsiveness and self-healing property are attracting extensive interest due to their enhanced performance for a wide range of applications. In this work, we have successfully developed novel hydrogels based on interfacial polymer-nanogel benzoxaborolate cross-linking at physiological pH. Temperature-sensitive nanogels (NG-Gal) containing galactose residues on the nanosurface were prepared and subsequently used as macro-cross-linkers to form a hydrogel network through formation of dynamic adducts with benzoxaborole groups of a hydrophilic copolymer poly(DMA--MAABO).

High-Throughput Ligand Screening Enables the Enantioselective Conjugate Borylation of Cyclobutenones to Access Synthetically Versatile Tertiary Cyclobutylboronates.

Cyclobutane rings are important in medicinal chemistry, yet few enantioselective methods exist to access this scaffold. In particular, cyclobutylboronates are receiving increasing attention in the literature due to the synthetic versatility of alkylboronic esters and the increasing role of boronic acids in drug discovery. Herein, a conjugate borylation of α-alkyl,β-aryl/alkyl cyclobutenones is reported leading to the first synthesis of enantioenriched tertiary cyclobutylboronates.

Two-component boronic acid catalysis for increased reactivity in challenging Friedel-Crafts alkylations with deactivated benzylic alcohols.

A general and efficient boronic acid catalyzed Friedel-Crafts alkylation of arenes with benzylic alcohols was previously developed for the construction of unsymmetrical diarylmethane products (X. Mo, J. Yakiwchuk, J.

Boronic acid catalysis.

Although boronic acids are recognized primarily for their utility as reagents in transition metal-catalyzed transformations, other applications are emerging, including their use as reaction catalysts. Few methods are available for the catalytic activation of hydroxy functional groups as a way to promote their direct transformation into useful products under mild conditions. To this end, the ability of boronic acids to form reversible covalent bonds with hydroxy groups can be exploited to enable both electrophilic and nucleophilic modes of activation in various organic reactions.

Bioinspired Self-Healing Hydrogel Based on Benzoxaborole-Catechol Dynamic Covalent Chemistry for 3D Cell Encapsulation.

Boronic ester, one typical example of dynamic covalent bonds, has presented great potential to prepare self-healing hydrogels. However, most of currently reported hydrogels based on boronic esters are formed at pH > 8, which impeded their further use in physiological conditions. In this study, we designed two kinds of zwitterionic copolymers with benzoxaborole and catechol pendant groups, respectively.

Diastereocontrolled Monoprotodeboronation of β-Sulfinimido gem-Bis(boronates): A General and Stereoselective Route to α,β-Disubstituted β-Aminoalkylboronates.

β-Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β-amino acids but few stereoselective methods exist for their preparation. The 1,2-addition of lithiated 1,1-diborylalkanes onto chiral N-tert-butanesulfinyl aldimines produces β-sulfinimido gem-bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents.

Valdecoxib vs. borazavaldecoxib: isoxazole BN/CC isosterism as a case study in designing and stabilizing boron heterocycles.

A comprehensive study on the preparation, hydrolytic stability, and the structural and spectrophotometric properties of 1,2,4,5-oxadiazaboroles is presented by way of a comparison between the NSAID drug valdecoxib (1) and its unprecedented B-N isostere, borazavaldecoxib (2). Knowledge gained from this study was employed in the design of oxadiazaborate salts, a novel class of tetrahedral boron heterocycles displaying good stability in aqueous conditions with promising antifungal and antibacterial properties.

Boronic Acids as Bioorthogonal Probes for Site-Selective Labeling of Proteins.

Over the past two decades, bioorthogonal chemistry has become a preferred tool to achieve site-selective modifications of proteins. However, there are only a handful of commonly applied bioorthogonal reactions and they display some limitations, such as slow rates, use of unstable or cytotoxic reagents, and side reactions. Hence, there is significant interest in expanding the bioorthogonal chemistry toolbox.