Design, Synthesis and Evaluation of Fe-S Targeted Adenosine 5′-Phosphosulfate Reductase Inhibitors

<div><p>Adenosine 5′-phosphosulfate reductase (APR) is an iron-sulfur enzyme that is vital for survival of <i>Mycobacterium tuberculosis</i> during dormancy and is an attractive target for the treatment of latent tuberculosis (TB) infection. The 4Fe-4S cluster is coordinated to APR by sulfur atoms of four cysteine residues, is proximal to substrate, adenosine 5′-phopsphosulfate (APS), and is essential for catalytic activity. Herein, we present an approach for the development of a new class of APR inhibitors. As an initial step, we have employed an improved solid-phase chemistry method to prepare a series of <i>N</i>⁶-substituted adenosine analogues and their 5′-phosphates as well as adenosine 5′-phosphate diesters bearing different Fe and S binding groups, such as thiols or carboxylic and hydroxamic acid moieties. Evaluation of the resulting compounds indicates a clearly defined spacing requirement between the Fe-S targeting group and adenosine scaffold and that smaller Fe-S targeting groups are better tolerated. Molecular docking analysis suggests that the S atom of the most potent inhibitor may establish a favorable interaction with an S atom in the cluster. In summary, this study showcases an improved solid-phase method that expedites the preparation of adenosine and related 5′-phosphate derivatives and presents a unique Fe-S targeting strategy for the development of APR inhibitors.</p></div

Asymmetric Synthesis of Chiral 9,10-Dihydrophenanthrenes Using Pd-Catalyzed Asymmetric Intramolecular Friedel–Crafts Allylic Alkylation of Phenols

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel–Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee

Media 1: Continuous scanning of a time-reversed ultrasonically encoded optical focus by reflection-mode digital phase conjugation

Originally published in Optics Letters on 15 June 2014 (ol-39-12-3441

Concise Enantioselective Synthesis of Duloxetine via Direct Catalytic Asymmetric Aldol Reaction of Thioamide

Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH₄ reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine

Asymmetric Synthesis of Chiral 9,10-Dihydrophenanthrenes Using Pd-Catalyzed Asymmetric Intramolecular Friedel–Crafts Allylic Alkylation of Phenols

We developed a novel asymmetric synthetic method for multisubstituted 9,10-dihydrophenanthrenes based on the Pd-catalyzed asymmetric intramolecular Friedel–Crafts allylic alkylation of phenols, which produces 10-vinyl or 10-isopropenyl chiral 9,10-dihydrophenanthrene derivatives in high yield with up to 94% ee

Photoelectron Imaging Signature for Selective Formation of Icosahedral Anionic Silver Cages Encapsulating Group 5 Elements: M@Ag₁₂^– (M = V, Nb, and Ta)

An assembly of 13 atoms can form highly symmetric architectures like those belonging to D3h, Oh, D5h, and Ih point groups. Here, using photoelectron imaging spectroscopy in combination with density functional theory (DFT) calculations, we present a simple yet convincing experimental signature for the selective formation of icosahedral cages of anionic silver clusters encapsulating a dopant atom of group 5 elements: M@Ag12– (M = V, Nb, and Ta). Their photoelectron images obtained at 4 eV closely resemble one another: only a single ring is observed, which is assignable to photodetachment signals from a 5-fold degenerate superatomic 1D electronic shell in the 1S21P61D10 configuration of valence electrons. The perfect degeneracy represents an unambiguous fingerprint of an icosahedral symmetry, which would otherwise be lifted in all of the other structural isomers. DFT calculations confirm that Ih forms are the most stable and that D5h, Oh, and D3h structures are not found even in metastable states

Photoelectron Imaging Signature for Selective Formation of Icosahedral Anionic Silver Cages Encapsulating Group 5 Elements: M@Ag₁₂^– (M = V, Nb, and Ta)

An assembly of 13 atoms can form highly symmetric architectures like those belonging to D3h, Oh, D5h, and Ih point groups. Here, using photoelectron imaging spectroscopy in combination with density functional theory (DFT) calculations, we present a simple yet convincing experimental signature for the selective formation of icosahedral cages of anionic silver clusters encapsulating a dopant atom of group 5 elements: M@Ag12– (M = V, Nb, and Ta). Their photoelectron images obtained at 4 eV closely resemble one another: only a single ring is observed, which is assignable to photodetachment signals from a 5-fold degenerate superatomic 1D electronic shell in the 1S21P61D10 configuration of valence electrons. The perfect degeneracy represents an unambiguous fingerprint of an icosahedral symmetry, which would otherwise be lifted in all of the other structural isomers. DFT calculations confirm that Ih forms are the most stable and that D5h, Oh, and D3h structures are not found even in metastable states

Alternative Pathways of Human Islet Amyloid Polypeptide Aggregation Distinguished by ¹⁹F Nuclear Magnetic Resonance-Detected Kinetics of Monomer Consumption

Amyloid formation, a complex process involving many intermediate states, is proposed to be the driving force for amyloid-related toxicity in common degenerative diseases. Unfortunately, the details of this process have been obscured by the limitations in the methods that can follow this reaction in real time. We show that alternative pathways of aggregation can be distinguished by using ¹⁹F nuclear magnetic resonance (NMR) to monitor monomer consumption along with complementary measurements of fibrillogenesis. The utility of this technique is demonstrated by tracking amyloid formation in the diabetes-related islet amyloid polypeptide (IAPP). Using this technique, we show IAPP fibrillizes without an appreciable buildup of nonfibrillar intermediates, in contrast to the well-studied Aβ and α-synuclein proteins. To further develop the usage of ¹⁹F NMR, we have tracked the influence of the polyphenolic amyloid inhibitor epigallocatechin gallate (EGCG) on the aggregation pathway. Polyphenols have been shown to strongly inhibit amyloid formation in many systems. However, spectroscopic measurements of amyloid inhibition by these compounds can be severely compromised by background signals and competitive binding with extrinsic probes. Using ¹⁹F NMR, we show that thioflavin T strongly competes with EGCG for binding sites on IAPP fibers. By comparing the rates of monomer consumption and fiber formation, we are able to show that EGCG stabilizes nonfibrillar large aggregates during fibrillogenesis

New Route of Acetylene Synthesis via Electrochemical Formation of Metal Carbides from CO₂ in Chloride Melts

Electrochemical conversion of CO2 in high-temperature molten salts provides a unique process for synthesizing materials that cannot be obtained in low-temperature aqueous systems. In this study, we propose a novel route to produce acetylene utilizing the electrochemical reduction of CO2 in chloride melts. Acetylene is generated by the reaction between water and metal carbides, which are formed by the reduction of CO2 and cations in the melts. We demonstrated the proposed process by electrochemical measurements and quantitative gas analysis. To investigate the electrolytic system suitable for forming Li2C2 and CaC2 as the metal carbides at high current efficiency, two types of melts: LiCl–KCl–CaCl2–CaO melt at 723 K and NaCl–KCl–CaCl2–CaO melt at 823 K, and two types of electrodes: metallic electrodes (Fe, SUS304, SUS316, Mo, Ta and Ti) and carbon electrodes (graphite, glassy carbon, and highly oriented pyrolytic graphite) were used. It was found that acetylene was obtained with a current efficiency of 68% by galvanostatic electrolysis at −200 mA cm–2 on a Fe electrode in the NaCl–KCl–CaCl2–CaO melt mixed with 7.0 mol % CaC2 under CO2 atmosphere. The CaC2 played a key role in preventing the dissolution of electrodeposited metal carbides into the melts

Resolution of Oligomeric Species during the Aggregation of Aβ_1–40 Using ¹⁹F NMR

In the commonly used nucleation-dependent model of protein aggregation, aggregation proceeds only after a lag phase in which the concentration of energetically unfavorable nuclei reaches a critical value. The formation of oligomeric species prior to aggregation can be difficult to detect by current spectroscopic techniques. By using real-time ¹⁹F NMR along with other techniques, we are able to show that multiple oligomeric species can be detected during the lag phase of Aβ_1–40 fiber formation, consistent with a complex mechanism of aggregation. At least six types of oligomers can be detected by ¹⁹F NMR. These include the reversible formation of large β-sheet oligomer immediately after solubilization at high peptide concentration, a small oligomer that forms transiently during the early stages of the lag phase, and four spectroscopically distinct forms of oligomers with molecular weights between ∼30 and 100 kDa that appear during the later stages of aggregation. The ability to resolve individual oligomers and track their formation in real-time should prove fruitful in understanding the aggregation of amyloidogenic proteins and in isolating potentially toxic nonamyloid oligomers