Intermolecular Homopropargyl Alcohol Addition to Alkyne and a Sequential 1,6-Enyne Cycloisomerization with Triazole-Gold Catalyst

While gold-catalyzed homopropargyl alcohol cyclization is a known process, a triazole-gold catalyst prevented the intramolecular cyclization in the presence of terminal alkynes. As a result, an intermolecular addition to an alkyne was achieved. A sequential 1,6-enyne cycloisomerization gave the unusual 2,3-dihydrooxepine, which revealed another new reaction path. Diels–Alder reaction of oxepine followed by a 1,3-alkoxyl shift gave hydrobezofuran derivatives in high yields. Diasterioselective reaction of homopropargyl alcohol to final product enabled one-step formation of five stereogenic centers with excellent enantiomeric selectivity

Synthesis and Characterization of Bis‑<i>N</i>‑2-Aryl Triazole as a Fluorophore

Naphthalene-bridged bis-triazole (NBT) complexes were prepared and characterized for investigation of their photophysical properties. Unlike our previously reported <i>N</i>-2-aryl triazoles, which gave strong emissions through the planar intramolecular charge transfer mechanism (coplanar conformation), this newly developed NBT adopted a noncoplanar conformation between triazole and naphthalene, achieving fluorescence through twisted intramolecular charge transfer

Fluorogenic Probe for the Human Ether-a-Go-Go-Related Gene Potassium Channel Imaging

The first small-molecule fluorogenic probe A1 for imaging the human Ether-a-go-go-Related Gene (hERG) potassium channel based on the photoinduced electron transfer (PET) off–on mechanism was described herein. After careful biological evaluation, this probe had the potential of detecting and imaging the hERG channel at the molecular and cellular level. Moreover, the competitive binding mechanism of this probe would presumably minimize the effects on the electrophysiological properties of the hERG channel. Therefore, this probe may serve as a powerful toolkit to the hERG-associated study

Bioluminescent Probe for Detecting Mercury(II) in Living Mice

A novel bioluminescence probe for mercury­(II) was obtained on the basis of the distinct deprotection reaction of dithioacetal to decanal, so as to display suitable sensitivity and selectivity toward mercury­(II) over other ions with bacterial bioluminescence signal. These experimental results indicated such a probe was a novel promising method for mercury­(II) bioluminescence imaging in environmental and life sciences ex vivo and in vivo

How to Improve Docking Accuracy of AutoDock4.2: A Case Study Using Different Electrostatic Potentials

Molecular docking, which is the indispensable emphasis in predicting binding conformations and energies of ligands to receptors, constructs the high-throughput virtual screening available. So far, increasingly numerous molecular docking programs have been released, and among them, AutoDock 4.2 is a widely used docking program with exceptional accuracy. It has heretofore been substantiated that the calculation of partial charge is very fundamental for the accurate conformation search and binding energy estimation. However, no systematic comparison of the significances of electrostatic potentials on docking accuracy of AutoDock 4.2 has been determined. In this paper, nine different charge-assigning methods, including AM1-BCC, Del-Re, formal, Gasteiger–Hückel, Gasteiger–Marsili, Hückel, Merck molecular force field (MMFF), and Pullman, as well as the ab initio Hartree–Fock charge, were sufficiently explored for their molecular docking performance by using AutoDock4.2. The results clearly demonstrated that the empirical Gasteiger–Hückel charge is the most applicable in virtual screening for large database; meanwhile, the semiempirical AM1-BCC charge is practicable in lead compound optimization as well as accurate virtual screening for small databases

Biodegradable Polymer Nanoparticles for Photodynamic Therapy by Bioluminescence Resonance Energy Transfer

Conventional photodynamic therapy is severely constrained by the limited light-penetration depth in tissue. Here, we show efficient photodynamic therapy (PDT) mediated by bioluminescence resonance energy transfer (BRET) that overcomes the light-penetration limitation. The photosensitizer Rose Bengal (RB) was loaded in biodegradable poly­(lactic-<i>co</i>-glycolic acid) (PLGA) nanoparticles, which were then conjugated with firefly luciferase. Spectroscopic characterizations indicated that BRET effectively activated RB to generate reactive oxygen species (ROS). In vitro studies of the cellular cytotoxicity and photodynamic effect indicated that cancer cells were effectively destroyed by BRET-PDT treatment. In vivo studies in a tumor-bearing mouse model demonstrated that tumor growth was significantly inhibited by BRET-PDT in the absence of external light irradiation. The BRET-mediated phototherapy provides a promising approach to overcome the light-penetration limitation in photodynamic treatment of deep-seated tumors

Discovery of Quinazoline-Based Fluorescent Probes to α₁‑Adrenergic Receptors

α₁-Adrenergic receptors (α₁-ARs), as the essential members of G protein-coupled receptors (GPCRs), can mediate numerous physiological responses in the sympathetic nervous system. In the current research, a series of quinazoline-based small-molecule fluorescent probes to α₁-ARs (<b>1a</b>–<b>1e</b>), including two parts, a pharmacophore for α₁-AR recognition and a fluorophore for visualization, were well designed and synthesized. The biological evaluation results displayed that these probes held reasonable fluorescent properties, high affinity, accepted cell toxicity, and excellent subcellular localization imaging potential for α₁-ARs

Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC₅₀ values (1.8–1.9 μM). Further studies demonstrated that compound <b>H8-A5</b> was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for <b>H8-A5</b>, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment

Discovery of Bioluminogenic Probes for Aminopeptidase N Imaging

To find an approach that can image the hydrolysis activity of aminopeptidase N (APN) both <i>in vitro</i> and <i>in vivo</i>, three bioluminescent probes have been well designed and synthesized herein. All of them can be recognized and hydrolyzed by APN to produce bioluminescence emission in the presence of firefly luciferase. To the best of our knowledge, they are the first bioluminescent probes for imaging APN in deep tissues and living animals