Enantioselective Total Synthesis of (+)-Amabiline

The first total synthesis of (+)-amabiline, an unsaturated pyrrolizidine alkaloid from <i>Cynoglossum amabile</i>, is reported. This convergent, enantioselective synthesis proceeds in 15 steps (10-step longest linear sequence) in 6.2% overall yield and features novel methodology to construct the unsaturated pyrrolizidine or (−)-supinidine core

Visible-Light-Driven Photocatalytic Initiation of Radical Thiol–Ene Reactions Using Bismuth Oxide

A nontoxic and inexpensive photocatalytic initiation of anti-Markovnikov hydrothiolation of olefins using visible light is reported. This method is characterized by low catalyst loading, thereby enabling a mild and selective method for radical initiation in thiol–ene reactions between a wide scope of olefins and thiols

Covalent Enzyme Inhibition through Fluorosulfate Modification of a Noncatalytic Serine Residue

Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (<i>e.g.</i>, acrylamide) on the ligand template. However, cysteine residues are not always available for site-specific protein labeling, and therefore new approaches are needed to expand the toolkit of appropriate electrophiles (“warheads”) that target alternative amino acids. We previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with a sulfonyl fluoride electrophile. These inhibitors subsequently enabled the development of clickable probe technology to measure drug-target occupancy in live cells. Here we describe a fluorosulfate-containing inhibitor (aryl fluorosulfate probe (FS-p1)) with excellent chemical and metabolic stability that reacts selectively with a noncatalytic serine residue in the same active site of DcpS as confirmed by peptide mapping experiments. Our results suggest that noncatalytic serine targeting using fluorosulfate electrophilic warheads could be a suitable strategy for the development of covalent inhibitor drugs and chemical probes

μMap Photoproximity Labeling Enables Small Molecule Binding Site Mapping

The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of target binding regions is typically achieved by X-ray crystallography or photoaffinity labeling (PAL) approaches; yet, these methods present significant challenges. X-ray crystallography is a mainstay technique that has revolutionized drug discovery, but in many cases structural characterization is challenging or impossible. PAL has also enabled binding site mapping with peptide- and amino-acid-level resolution; however, the stoichiometric activation mode can lead to poor signal and coverage of the resident binding pocket. Additionally, each PAL probe can have its own fragmentation pattern, complicating the analysis by mass spectrometry. Here, we establish a robust and general photocatalytic approach toward the mapping of protein binding sites, which we define as identification of residues proximal to the ligand binding pocket. By utilizing a catalytic mode of activation, we obtain sets of labeled amino acids in the proximity of the target protein binding site. We use this methodology to map, in vitro, the binding sites of six protein targets, including several kinases and molecular glue targets, and furthermore to investigate the binding site of the STAT3 inhibitor MM-206, a ligand with no known crystal structure. Finally, we demonstrate the successful mapping of drug binding sites in live cells. These results establish μMap as a powerful method for the generation of amino-acid- and peptide-level target engagement data

μMap Photoproximity Labeling Enables Small Molecule Binding Site Mapping

The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of target binding regions is typically achieved by X-ray crystallography or photoaffinity labeling (PAL) approaches; yet, these methods present significant challenges. X-ray crystallography is a mainstay technique that has revolutionized drug discovery, but in many cases structural characterization is challenging or impossible. PAL has also enabled binding site mapping with peptide- and amino-acid-level resolution; however, the stoichiometric activation mode can lead to poor signal and coverage of the resident binding pocket. Additionally, each PAL probe can have its own fragmentation pattern, complicating the analysis by mass spectrometry. Here, we establish a robust and general photocatalytic approach toward the mapping of protein binding sites, which we define as identification of residues proximal to the ligand binding pocket. By utilizing a catalytic mode of activation, we obtain sets of labeled amino acids in the proximity of the target protein binding site. We use this methodology to map, in vitro, the binding sites of six protein targets, including several kinases and molecular glue targets, and furthermore to investigate the binding site of the STAT3 inhibitor MM-206, a ligand with no known crystal structure. Finally, we demonstrate the successful mapping of drug binding sites in live cells. These results establish μMap as a powerful method for the generation of amino-acid- and peptide-level target engagement data

μMap Photoproximity Labeling Enables Small Molecule Binding Site Mapping

The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of target binding regions is typically achieved by X-ray crystallography or photoaffinity labeling (PAL) approaches; yet, these methods present significant challenges. X-ray crystallography is a mainstay technique that has revolutionized drug discovery, but in many cases structural characterization is challenging or impossible. PAL has also enabled binding site mapping with peptide- and amino-acid-level resolution; however, the stoichiometric activation mode can lead to poor signal and coverage of the resident binding pocket. Additionally, each PAL probe can have its own fragmentation pattern, complicating the analysis by mass spectrometry. Here, we establish a robust and general photocatalytic approach toward the mapping of protein binding sites, which we define as identification of residues proximal to the ligand binding pocket. By utilizing a catalytic mode of activation, we obtain sets of labeled amino acids in the proximity of the target protein binding site. We use this methodology to map, in vitro, the binding sites of six protein targets, including several kinases and molecular glue targets, and furthermore to investigate the binding site of the STAT3 inhibitor MM-206, a ligand with no known crystal structure. Finally, we demonstrate the successful mapping of drug binding sites in live cells. These results establish μMap as a powerful method for the generation of amino-acid- and peptide-level target engagement data

μMap Photoproximity Labeling Enables Small Molecule Binding Site Mapping

The characterization of ligand binding modes is a crucial step in the drug discovery process and is especially important in campaigns arising from phenotypic screening, where the protein target and binding mode are unknown at the outset. Elucidation of target binding regions is typically achieved by X-ray crystallography or photoaffinity labeling (PAL) approaches; yet, these methods present significant challenges. X-ray crystallography is a mainstay technique that has revolutionized drug discovery, but in many cases structural characterization is challenging or impossible. PAL has also enabled binding site mapping with peptide- and amino-acid-level resolution; however, the stoichiometric activation mode can lead to poor signal and coverage of the resident binding pocket. Additionally, each PAL probe can have its own fragmentation pattern, complicating the analysis by mass spectrometry. Here, we establish a robust and general photocatalytic approach toward the mapping of protein binding sites, which we define as identification of residues proximal to the ligand binding pocket. By utilizing a catalytic mode of activation, we obtain sets of labeled amino acids in the proximity of the target protein binding site. We use this methodology to map, in vitro, the binding sites of six protein targets, including several kinases and molecular glue targets, and furthermore to investigate the binding site of the STAT3 inhibitor MM-206, a ligand with no known crystal structure. Finally, we demonstrate the successful mapping of drug binding sites in live cells. These results establish μMap as a powerful method for the generation of amino-acid- and peptide-level target engagement data

Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]­pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound <b>7</b>, a potent AR (ARE EC₅₀ = 0.34 nM) and selective (N/C interaction EC₅₀ = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of <b>7</b>, and further insights from modeling studies of ligand receptor interactions are also presented

Structure-Based Approach To Identify 5‑[4-Hydroxyphenyl]­pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound <b>7</b>, a potent AR (ARE EC₅₀ = 0.34 nM) and selective (N/C interaction EC₅₀ = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of <b>7</b>, and further insights from modeling studies of ligand receptor interactions are also presented

The Faculty of education restaurant consumers' attitude towards the responsible treatment of food

Food waste is a burning issue all over the world. Different producers, households, shops, restaurants, schools and other food offering venues face this problem. It is important to raise the society’s awareness about the consequences of food waste. In my diploma work I tried to establish the secondary school students and the students of the Faculty of Education attitude towards food and the level of their satisfaction with the faculty restaurant food. I have researched the reasons for the food waste and gathered students’ suggestions on how to reduce its amount. In my research, I have used a descriptive method and a quantitative approach. There were 60 students of the Faculty of Education and 59 secondary school students of the Pre-school Teacher Training Secondary School participating in my research. The research showed a moderate level of student’s satisfaction with the food in the restaurant at the Faculty of Education. The main reasons in case of dissatisfaction are according to students the taste and general food quality. I discovered that one of the main reasons for food waste are large portions but the students claimed the reason for not finishing the meal was the feeling of satiety. The secondary school students usually finish their meals whereas the college students more often leave some food on their plates. They have both suggested that food waste could be reduced by giving them smaller portions which means they should be able to choose the size of the meal at the self-service counter. They also proposed that users of food services could be educated about food waste problem through various lectures and education programs. They suggested the use of available food containers for the left-overs and extra food that could be given to those who are in need. Communication between the service providers and users is also very important as it can greatly reduce the number of times when less desired foods are offered. The awareness about discarded food is increasingly rising in schools and colleges. According to the results of my research, I estimated that secondary school students and college students are both conscious of the consequences of discarded food with college students being slightly more aware of the problem. My estimation is that the amount of food waste can be reduced by careful planning and management of offered foods. Different projects that would raise the awareness about food waste among the student population are also very important