Using Ligand-Accelerated Catalysis to Repurpose Fluorogenic Reactions for Platinum or Copper.

The development of a fluorescent probe for a specific metal has required exquisite design, synthesis, and optimization of fluorogenic molecules endowed with chelating moieties with heteroatoms. These probes are generally chelation- or reactivity-based. Catalysis-based fluorescent probes have the potential to be more sensitive; however, catalytic methods with a biocompatible fluorescence turn-on switch are rare. Here, we have exploited ligand-accelerated metal catalysis to repurpose known fluorescent probes for different metals, a new approach in probe development. We used the cleavage of allylic and propargylic ethers as platforms that were previously designed for palladium. After a single experiment that combinatorially examined >800 reactions with two variables (metal and ligand) for each ether, we discovered a platinum- or copper-selective method with the ligand effect of specific phosphines. Both metal-ligand systems were previously unknown and afforded strong signals owing to catalytic turnover. The fluorometric technologies were applied to geological, pharmaceutical, serum, and live cell samples and were used to discover that platinum accumulates in lysosomes in cisplatin-resistant cells in a manner that appears to be independent of copper distribution. The use of ligand-accelerated catalysis may present a new blueprint for engineering metal selectivity in probe development.

Fluorogenic Probe Using a Mislow-Evans Rearrangement for Real-Time Imaging of Hydrogen Peroxide.

Hydrogen peroxide (H2 O2 ) mediates the biology of wound healing, apoptosis, inflammation, etc. H2 O2 has been fluorometrically imaged with protein- or small-molecule-based probes. However, only protein-based probes have afforded temporal insights within seconds. Small-molecule-based electrophilic probes for H2 O2 require many minutes for a sufficient response in biological systems. Here, we report a fluorogenic probe that selectively undergoes a [2,3]-sigmatropic rearrangement (seleno-Mislow-Evans rearrangement) with H2 O2 , followed by acetal hydrolysis, to produce a green fluorescent molecule in seconds. Unlike other electrophilic probes, the current probe acts as a nucleophile. The fast kinetics enabled real-time imaging of H2 O2 produced in endothelial cells in 8 seconds (much earlier than previously shown) and H2 O2 in a zebrafish wound healing model. This work may provide a platform for endogenous H2 O2 detection in real time with chemical probes.

Discoveries, target identifications, and biological applications of natural products that inhibit splicing factor 3B subunit 1.

Covering: 1992 to 2015The natural products FR901464, pladienolide, and herboxidiene were discovered as activators of reporter gene systems. Unexpectedly, these compounds target neither transcription nor translation; rather, they target splicing factor 3B subunit 1 of the spliceosome, causing changes in splicing patterns. All of them showed anticancer activity in a low nanomolar range. Since their discovery, these molecules have been used in a variety of biological applications.

Fluorometric imaging methods for palladium and platinum and the use of palladium for imaging biomolecules.

Neither palladium nor platinum is an endogenous biological metal. Imaging palladium in biological samples, however, is becoming increasingly important because bioorthogonal organometallic chemistry involves palladium catalysis. In addition to being an imaging target, palladium has been used to fluorometrically image biomolecules. In these cases, palladium species are used as imaging-enabling reagents. This review article discusses these fluorometric methods. Platinum-based drugs are widely used as anticancer drugs, yet their mechanism of action remains largely unknown. We discuss fluorometric methods for imaging or quantifying platinum in cells or biofluids. These methods include the use of chemosensors to directly detect platinum, fluorescently tagging platinum-based drugs, and utilizing post-labeling to elucidate distribution and mode of action.

False tendons: an endoscopic cadaveric approach.

False tendons (FTs) have been extensively described and recognized by gross anatomic studies. However, in the clinical setting the recognition of FTs is limited to the use of echocardiography. We examined 200 formalin fixed adult hearts, with gross dissections. In addition, 90 of these specimens were also examined with ultrasonographic and endoscopic techniques. Gross examination was able to identify FTs in 128 (62%) specimens. The total number of FTs observed, was 248 and was classified into five types according to their location. In Type I (92, 37.1%) the FT was located between the posteromedial papillary muscle and the ventricular septum. In Type II (55, 22.1%) the FT was located between the two papillary muscles. Type III (41, 16.5%) was classified as an FT between the anterolateral papillary muscle and the ventricular septum. The FT in Type IV (31, 12.5%) was observed to connect between the ventricular septum and the free wall and lastly in Type V (29, 11.6%) the FTs were found to be weblike with three or more points of insertion. When using all three techniques (n = 90), gross dissection and endoscopy were able to identify FTs in 62.2% of specimens while echocardiographic imaging was only able to identify FTs in 27.7% of specimens. Of the 114 FTs detected grossly and endoscopically, echocardiography was only able to identify 46 (40.3%). Therefore, the overall sensitivity of echocardiography for detecting left ventricular FTs was only 40.3%, compared to 100% for endoscopy. Based upon the ability or lack thereof of echocardiography to detect certain topographical patterns, we have created a small series of subtypes for the FTs. Histologically, in 30% of the FTs, conduction tissue fiber was observed to be present, which may implicate them in the appearance of arrhythmias.