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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. Using molecular dynamics (MD) simulations, we assessed the binding site and affinity of GE11 for EGFR. The GE11-modified micelles, tagged with a near-infrared fluorophore, showed enhanced internalization by EGFR-overexpressing CRC cells

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 Bronsted 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. Here, these questions are addressed with a combination of experimental, spectroscopic, X-ray crystallographic, and computational studies of a series of model benzoxazaborine and benzodiazaborine naphthoids. Although these hemiboronic heterocycles are unambiguously shown to behave as Lewis acids in aqueous solutions, boraza derivatives possess partial aromaticity provided their nitrogen lone electron pair is sufficiently available to participate in extended delocalization. As demonstrated by dynamic exchange and crossover experiments, these heterocycles are stable in neutral aqueous medium, and their measured pKa values are consistent with the ability of the endocyclic heteroatom substituent to stabilize a partial negative charge in the conjugate base. Altogether, this study corrects previous inaccuracies and provides conclusions regarding the properties of these compounds that are important toward the methodical application of hemiboronic and other boron heterocycles in catalysis, bioconjugation, and medicinal chemistry.

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. These questions are addressed with a combination of physical and spectroscopic characterizations, X-ray crystallographic analysis, and computational studies. Although both oxa and aza derivatives are conclusively shown to behave as Lewis acids in aqueous solutions, according to p

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. Acylation of the DAN system causes a localization of both HOMO and LUMO onto the DNK unit, which validates the negligible influence of the B-aryl substituent. The LUMO energy is lowered, and its shape significantly altered. Photophysical data in solution and the solid state revealed blue-shifted, narrowed, and intense emissions for DNKs (up to 89 % quantum yield). The potential utility of the fluorogenic DNK system was demonstrated with a proof-of-concept for the determination of trace boronic acid contaminants in solid samples, down to one-ppm level, using HPLC with fluorescence detection. This method could be useful in pharmaceutical development for the quantitation of difficult-to-detect and potentially mutagenic residual boronic acid from late cross-coupling reactions in drug syntheses.

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. Here, we report on the in vitro and in vivo evaluation of a nano-encapsulated potent, but poorly water-soluble lead PNKP inhibitor, A83B4C63, as a new targeted therapeutic for PTEN-deficient CRC. Our data confirmed the binding of A83B4C63, as free or nanoparticle (NP) formulation, to intracellular PNKP using the cellular thermal shift assay (CETSA), in vitro and in vivo. Dose escalating toxicity studies in healthy CD-1 mice, based on measurement of animal weight changes and biochemical blood analysis, revealed the safety of both free and nano-encapsulated A83B4C63, at assessed doses of ≤50 mg/kg. Nano-carriers of A83B4C63 effectively inhibited the growth of HCT116/PTEN−/− xenografts in NIH-III nude mice following intravenous (IV) administration, but not that of wild-type HCT116/PTEN+/+ xenografts. This was in contrast to IV administration of A83B4C63 solubilized with the aid of Cremophor EL: Ethanol (CE), which led to similar tumor growth to that of formulation excipients (NP or CE without drug) or 5% dextrose. This observation was attributed to the higher levels of A83B4C63 delivered to tumor tissue by its NP formulation. Our data provide evidence for the success of NPs of A83B4C63, as novel synthetically lethal nano-therapeutics in the treatment of PTEN-deficient CRC. This research also highlights the potential of successful application of nanomedicine in the drug development process.

Oxidative amidation chemistry provides a unified route to aromatic Erythrina alkaloids through a sequence that illustrates new principles and improved conditions to effect a crucial eliminative Curtius–Schmidt rearrangement.