Medium-sized heterocycles exist in a broad spectrum of biologically active natural products and medicinally important synthetic compounds. The construction of medium-sized rings remains challenging, particularly the assembly of different ring sizes from the same type of substrate. Here we report palladium-catalyzed, regiodivergent [5 + 4] and [5 + 2] annulations of vinylethylene carbonates and allylidenemalononitriles. We describe the production of over 50 examples of nine- and seven-membered heterocycles in high isolated yields and excellent regioselectivities. We demonstrate the synthetic utility of this approach by converting a nine-membered ring product to an interesting polycyclic caged molecule via a [2 + 2] transannulation. Mechanistic studies suggest that the [5 + 2] annulation proceeds through palladium-catalyzed ring-opening/re-cyclization from the [5 + 4] adducts.

/pdf/regiodivergent-construction-of-medium-sized-heterocycles-5gohd76blu.pdf

Regiodivergent construction of medium-sized heterocycles from vinylethylene carbonates and allylidenemalononitriles

19F NMR has emerged as a powerful tool in drug discovery, particularly in fragment-based screens. The favorable magnetic resonance properties of the fluorine-19 nucleus, the general absence of fluorine in biological settings, and its ready incorporation into both small molecules and biopolymers, has enabled multiple applications of 19F NMR using labeled small molecules and proteins in biophysical, biochemical, and cellular experiments. This review will cover developments in ligand-observed and protein-observed 19F NMR experiments tailored towards drug discovery with a focus on fragment screening. We also cover the key advances that have furthered the field in recent years, including quantitative, structural, and in-cell methodologies. Several case studies are described for each application to highlight areas for innovation and to further catalyze new NMR developments for using this versatile nucleus.

/pdf/19f-nmr-viewed-through-two-different-lenses-ligand-observed-spsp1de0vt.pdf

19F NMR viewed through two different lenses: ligand-observed and protein-observed 19F NMR applications for fragment-based drug discovery.

Magnetic resonance techniques are successfully utilized in a broad range of scientific disciplines and in various practical applications, with medical magnetic resonance imaging being the most widely known example. Currently, both fundamental and applied magnetic resonance are enjoying a major boost owing to the rapidly developing field of spin hyperpolarization. Hyperpolarization techniques are able to enhance signal intensities in magnetic resonance by several orders of magnitude, and thus to largely overcome its major disadvantage of relatively low sensitivity. This provides new impetus for existing applications of magnetic resonance and opens the gates to exciting new possibilities. In this review, we provide a unified picture of the many methods and techniques that fall under the umbrella term “hyperpolarization” but are currently seldom perceived as integral parts of the same field. Specifically, before delving into the individual techniques, we provide a detailed analysis of the underlying principles of spin hyperpolarization. We attempt to uncover and classify the origins of hyperpolarization, to establish its sources and the specific mechanisms that enable the flow of polarization from a source to the target spins. We then give a more detailed analysis of individual hyperpolarization techniques: the mechanisms by which they work, fundamental and technical requirements, characteristic applications, unresolved issues, and possible future directions. We are seeing a continuous growth of activity in the field of spin hyperpolarization, and we expect the field to flourish as new and improved hyperpolarization techniques are implemented. Some key areas for development are in prolonging polarization lifetimes, making hyperpolarization techniques more generally applicable to chemical/biological systems, reducing the technical and equipment requirements, and creating more efficient excitation and detection schemes. We hope this review will facilitate the sharing of knowledge between subfields within the broad topic of hyperpolarization, to help overcome existing challenges in magnetic resonance and enable novel applications.

Spin Hyperpolarization in Modern Magnetic Resonance

http://www.cell.com/article/S0969212621003373/pdf

Small, but powerful and attractive: 19F in biomolecular NMR

Microbial infections caused by a variety of drug-resistant microorganisms are more common, but there are fewer and fewer approved new antimicrobial chemotherapeutics for systemic administration capable of acting against these resistant infectious pathogens. Formulation innovations of existing drugs are gaining prominence, while the application of nanotechnologies is a useful alternative for improving/increasing the effect of existing antimicrobial drugs. Nanomaterials represent one of the possible strategies to address this unfortunate situation. This review aims to summarize the most current results of nanoformulations of antibiotics and antibacterial active nanomaterials. Nanoformulations of antimicrobial peptides, synergistic combinations of antimicrobial-active agents with nitric oxide donors or combinations of small organic molecules or polymers with metals, metal oxides or metalloids are discussed as well. The mechanisms of actions of selected nanoformulations, including systems with magnetic, photothermal or photodynamic effects, are briefly described.

/pdf/advances-in-nanostructures-for-antimicrobial-therapy-1nhe482s.pdf

Advances in Nanostructures for Antimicrobial Therapy

The design of new materials requires a deep understanding of the intricacies underpinning their structure-property relationships. These relationships are modified through synthesis and processing t...

/pdf/dynamic-nuclear-polarization-dnp-101-a-new-era-for-materials-1zicastk7e.pdf

Dynamic Nuclear Polarization (DNP) 101: A New Era for Materials

Chitosan nanocrystals synthesis via aging and application towards alginate hydrogels for sustainable drug release

The development of calcium sensitizers for the treatment of systolic heart failure presents difficulties, including judging the optimal efficacy and the specificity to target cardiac muscle. The thin filament is an attractive target because cardiac troponin C (cTnC) is the site of calcium binding and the trigger for subsequent contraction. One widely studied calcium sensitizer is levosimendan. We have recently shown that when a covalent cTnC–levosimendan analogue is exchanged into cardiac muscle cells, they become constitutively active, demonstrating the potency of a covalent complex. We have also demonstrated that levosimendan reacts in vitro to form a reversible covalent thioimidate bond specifically with cysteine 84, unique to cTnC. In this study, we use mass spectrometry to show that the in vitro mechanism of action of levosimendan is consistent with an allosteric, reversible covalent inhibitor; to determine whether the presence of the cTnI switch peptide or changes in either Ca2+ concentration or pH ...

Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ.

Heart muscle contraction is regulated by Ca2+ binding to cardiac troponin C. This induces troponin I (cTnI) switch region binding to the regulatory domain of troponin C (cNTnC), pulling the cTnI in...

The Role of Electrostatics in the Mechanism of Cardiac Thin Filament Based Sensitizers

We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.

https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.9b00168

Brittney A. Klein

Papers

Dynamic Nuclear Polarization (DNP) 101: A New Era for Materials

Chitosan nanocrystals synthesis via aging and application towards alginate hydrogels for sustainable drug release

Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ.

The Role of Electrostatics in the Mechanism of Cardiac Thin Filament Based Sensitizers

Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds