Selective sensing of adenosine monophosphate (AMP) by a calix[6]triazolium-based colorimetric sensing ensemble.

Since adenosine monophosphate (AMP) is closely related to many diseases, the measurement of AMP is important for the diagnosis and treatment of related diseases. Among the AMP sensors reported thus far, sensors that selectively recognize AMP, not ADP or ATP, are rare, and complex experimental procedures and additional instruments are required for AMP recognition. We developed a colorimetric chemosensor using calix[6]triazolium (CT6) and intended to use it for the simple and rapid detection of AMP. Colorimetric AMP detection was established through an indicator displacement assay (IDA) in which CT6 and Brooker's merocyanine (BM) were used as receptors and indicators, respectively. The change in the absorption spectrum and color of BM showed that the binding affinity of CT6 to AMP conferred high selectivity to the developed colorimetric chemosensor. The developed IDA-based chemosensor was extended to fabricate a paper-based colorimetric device for visual measurement, and the paper-based device exhibited a selective response to AMP through a definite color change from yellow to magenta. This paper-based colorimetric device shows growth potential for onsite visual measurement of AMP.

Calix[n]triazolium based turn-on fluorescent sensing ensemble for selective adenosine monophosphate (AMP) detection.

A novel calix[n]triazolium was synthesized and exhibited excellent selectivity for AMP. The binding between calix[n]triazolium and chromenolate anions forms a non-fluorescent complex and the resulting supramolecular ensemble selectively detects AMP in water and induces "turn-on" fluorescence. The sensing platform is the first macrocyclic system to discriminate AMP from ADP and ATP through fluorescence changes.

Discovery of Novel Small-Molecule Antiangiogenesis Agents to Treat Diabetic Retinopathy.

Diabetic retinopathy is the leading cause of blindness which is associated with excessive angiogenesis. Using the structure of wondonin marine natural products, we previously created a scaffold to develop a novel type of antiangiogenesis agent that possesses minimized cytotoxicity. To overcome its poor pharmaceutical properties, we further modified the structure. A new scaffold was derived in which the stereogenic carbon was changed to nitrogen and the 1,2,3-triazole ring was replaced by an alkyl chain. By comparing the bioactivity versus cytotoxicity, compound 31 was selected, which has improved aqueous solubility and an enhanced selectivity index. Mechanistically, 31 suppressed angiopoietin-2 (ANGPT2) expression induced by high glucose in retinal cells and exhibited in vivo antiangiogenic activity in choroidal neovascularization and oxygen-induced retinopathy mouse models. These results suggest the potential of 31 as a lead to develop antiangiogenic small-molecule drugs to treat diabetic retinopathy and as a chemical tool to elucidate new mechanisms of angiogenesis.

Tannic acid-functionalized boron nitride nanosheets for theranostics.

Here, we report a tannic acid-Fe3+ coordination complex coating that confers magnetic resonance imaging (MRI) theranostic properties to inert nanomaterials. Boron nitride nanosheets (BNS), which lack magnetic field and light responsiveness, were used as a model nonfunctional nanomaterial. Among various catechol derivatives tested (i.e., dopamine, 3,4-dihydroxyphenylacetic acid, gallic acid, and tannic acid), a coating of tannic acid-Fe3+ coordination complex provided the highest magnetic field relaxivity and near infrared (NIR) laser light responsiveness. An in vitro study showed that KB tumor cells treated with tannic acid-Fe3+ coordination complex adsorbed on BNS (TA-Fe/BNS) exhibited higher T1-weighted magnetic resonance contrast compared with plain BNS, and BNS coated with tannic acid or Fe alone. NIR irradiation at 808 nm caused a significant increase in KB tumor cell death after treatment with TA-Fe/BNS compared with other treatments. In vivo MRI imaging revealed tumor accumulation of intravenously administered TA-Fe/BNS. Guided by MRI information, application of focused laser irradiation onto tumor tissues resulted in complete tumor ablation. These results support the potential of TA-Fe/BNS for MRI theranostics. Moreover, this study suggests the wide applicability of TA-Fe noncovalent coating as biocompatible and facile tool for converting nonfunctional early-generation nanomaterials into functional new nanomaterials, opening new opportunities for their use in translational biomedical applications such as MRI theranostics.

Crown ether-appended calix[2]triazolium[2]arene as a macrocyclic receptor for the recognition of the H2PO4- anion.

A crown ether-appended calix[2]triazolium[2]arene, which exhibits excellent selectivity for H2PO4- compared to other anions, has been designed and synthesized. The selectivity of the prepared receptor for H2PO4- is caused by the stabilization of H2PO4- by the neighboring triazolium hydrogen bond donors and crown ether hydrogen bond acceptors.

Expedient Synthesis of Alphitolic Acid and Its Naturally Occurring 2- O-Ester Derivatives.

The expedient synthesis of alphitolic acid (1) as well as its natural C-3-epimer and 2- O-ester derivatives was accomplished in a few steps from the readily commercially available betulin (9). A Rubottom oxidation delivered an α-hydroxy group in a stereo- and chemoselective manner. The diastereoselective reduction of the α-hydroxy ketone was key to accessing the 1,2-diol moiety of this class of natural products. Our concise and stereoselective synthetic protocol allowed the gram-scale synthesis of these natural products, which will facilitate future biological evaluations.

Synthesis of Quinolizinium-Type Heteroaromatics via a Carbene Intermediate.

An efficient synthesis of quinolizinium-type heteroaromatics by Pt(II)-catalyzed cyclization of 2-arylpyridine propargyl alcohol has been developed. The presence of a protic acid is crucial for the success of the reaction. Mechanistic studies disclosed that the reaction proceeds via a platinum-carbene intermediate. Additionally, the fluorescence properties of the synthesized heteroaromatics were investigated to provide perspectives for potential applications.

Calix[n]triazoles and Related Conformational Studies.

Calix[n]triazoles are developed as new derivatives in the calixarene family. Calixtriazole compounds 2-4 are synthesized using an iterative convergent strategy including an inter-/intramolecular copper(I)-catalyzed azide-alkyne cycloaddition reaction. Solid-state structures are clearly refined to give 1,2-alternate and partial cone conformations for calix[4]triazole and calix[5]triazole, respectively. Theoretical studies based on density functional theory (DFT) calculations indicated that intermolecular interactions are crucial in determining the conformers of the crystals, and the most stable conformers of calix[4]triazole, calix[5]triazole, and calix[6]triazole in the monomeric forms are 1,3-alternate, 1,3-alternate, and 1,3,5-alternate, respectively.

A calix[2]triazole[2]arene-based fluorescent chemosensor for probing the copper trafficking pathway in Wilson's disease.

A pyrenyl-appended calix[2]triazole[2]arene displaying excellent selectivity for Cu(2+) over other metal ions in pyrenyl excimer emission changes was synthesized. The binding mode with Cu(2+) was supported through nuclear magnetic resonance (NMR) studies and density functional theory (DFT) calculations. Fluorescence imaging demonstrates that this new copper sensor is capable of detecting intracellular copper in living cells. Furthermore, through colocalization of the probe with organelle trackers as a function of time, it was observed that copper initially accumulates in lysosomes and then decreases. These results provide evidence for a close relationship between copper and lysosomes in Wilson's disease. This system is the first Cu(2+) ion-induced fluorescent turn-on system used for imaging copper trafficking over time in a Wilson's disease model.

Bimodal calix[2]triazole[2]arene fluorescent ionophore.

Pyrene-appended calix[2]triazole[2]arene capable of bimodal sensing has been synthesized. Upon addition of Zn(2+) (or Cd(2+)), it selectively exhibits an enhanced monomeric emission (~13-20-fold) over other metal ions. On the other hand, it displays excellent selectivity for Fe(2+) over other metal ions (even over Fe(3+)) from the angle of excimeric emissions (10-fold enhancement). Density Functional Theory (DFT) based theoretical calculations distinguished the bimodal activity of the probe and supported the experimental observations.

Design and synthesis of piperidine-containing sphingoid base analogues.

We report an approach that allows the efficient synthesis of the designed sphingoid base analogues in which the conformational restriction is introduced by incorporation of a cyclic moiety between the 2-amino group and the C-4 carbon atom of the sphingoid base. Our synthesis features a tandem enyne/diene-ene metathesis reaction that provides access to the designed framework. The diene moiety of the metathesis product is stereoselectively elaborated for the synthesis of the designed analogues. The preliminary biological evaluation indicates that the designed constrained analogues are much more effective than prototype natural sphingoid bases at inhibiting cancer cell growth.

Synthesis of novel polyyne analogues of sphingoid base via an iterative acetylene homologation sequence.

The first syntheses of polyyne-containing sphingoid base analogues were achieved by employing our iterative strategy that uses a two-step acetylene homologation sequence. In this process, a bromoalkyne is homologated by one acetylene unit through a Pd-catalyzed cross-coupling with a TIPS-protected acetylene and a subsequent in situ AgF-mediated desilylative bromination. Repeating this homologation sequence followed by cross-coupling with the long-chained terminal acetylene provides access to the polyyne framework in good overall yields.

Expedient syntheses of antofine and cryptopleurine via intramolecular 1,3-dipolar cycloaddition.

The practical and expedient total syntheses of the representative phenanthroindolizidine and phenanthroquinolizidine alkaloids, antofine and cryptopleurine, are described. Construction of the pyrrolidine and piperidine ring of each alkaloid was achieved by using an intramolecular 1,3-dipolar cycloaddition of an azide onto an alkene and subsequent reduction of the resulting imine and aziridine.