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Piperazine rings are essential motifs frequently found in commercial drugs. However, synthetic methodologies are mainly limited to N-substituted piperazines, preventing structural diversity. Disclosed herein is a straightforward catalytic method for the synthesis of complex C-substituted piperazines based on an uncommon head-to-head coupling of easily prepared imines. This 100% atom-economic process allows the selective formation of a sole diastereoisomer, a broad substrate scope, and a good functional group tolerance employing a bench-stable iridium catalyst under mild reaction conditions. Key to the success is the addition of N-oxides to the reaction mixture, as they notably enhance the catalytic activity and selectivity., The generous financial support from MCIN/AEI/10.13039/501100011033 (PID2020-119512GB-I00) and Gobierno de Aragón/FEDER, EU (GA/FEDER, Reactivity and Catalysis Inorganic Chemistry Group, E50_20D) is gratefully acknowledged. A.M.G. is thankful for Grant IJC2018-035231-I funded by MCIN/AEI/10.13039/501100011033, and L.T. thanks MICIIN/FEDER for an FPI fellowship.

An asymmetric catalytic approach for the construction of C3-multifunctionalization α-hydroxy-β-amino pyridines has been reported. The products can be accessed by the modulation of two chiral catalysts independently in high yield and with good enantioselectivity. The method features mild reaction conditions and an excellent functional group tolerance. Biological activity analysis shows that the resulting products have a selective antiosteosarcoma activity on 143B cells.

The synthesis and biological assessment of neutral or cationic platinum group metal-based anticancer complexes have been extremely studied, whereas there are few reports on the corresponding zwitterionic complexes. Herein, the synthesis, characterization, and bioactivity of zwitterionic half-sandwich phosphine-imine iridium(III), rhodium(III), and ruthenium(II) complexes were presented. The sulfonated phosphine-imine ligand and a group of zwitterionic half-sandwich

The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.

London dispersion (LD) is attracting more and more attention in catalysis since LD is ubiquitously present and cumulative. Since dispersion is hard to grasp, recent research has concentrated mainly on the effect of LD in individual catalytic complexes or on the impact of dispersion energy donors (DEDs) on balance systems. The systematic transfer of LD effects onto confined and more complex systems in catalysis is still in its infancy, and no general approach for using DED residues in catalysis has emerged so far. Thus, on the example of asymmetric Brønsted acid catalyzed transfer hydrogenation of imines, we translated the findings of previously isolated balance systems onto confined catalytic intermediates, resulting in a systematic enhancement of stereoselectivity when employing DED-substituted substrates. As the imine substrate is present as

Hydroxymethylation of α-branchediN/i-itert/i-butanesulfinyl ketimines with formaldehyde equivalents was developed to stereoselectively construct acyclic quaternary stereocenters bearing two sterically and electronically similar substituents. The stereoselectiveit/iBuOK-promoted α-deprotonation of acyclic ketimines allowed for the stereodefined formation of fully substituted aza-enolates, followed by facially selective C-C bond formation involving formaldehyde formediin situ/i, yielding α-hydroxymethylated products with precise stereocontrol.

Enantioselective imine reduction of dihydro-β-carbolines (DHBCs) is a reliable and powerful tool to construct bioactive chiral tetrahydro-β-carbolines (THBCs). Here, we report an efficient enantioselective imine reduction employingiin situ/igenerated Fe-thiosquaramides (Fe-TSQs)b3a/bandb3b/bas asymmetric organometallic catalysts to produce chiral THBCs (b2a/b-bh/b). The catalystb3a/bat 15 mol % was found to be suitable for the substrates with alkyl and aryl groups which afford corresponding chiral THBCs with excellent enantioselectivities (up to ee 99%).

Relationships between chemical structure and conductivity in ordered polymers (OPs) are difficult to probe using bulk samples. We propose that conductance measurements of appropriate molecular-scale models can reveal trends in electronic coupling(s) between repeat units that may help inform OP design. Here, we apply the scanning tunneling microscope-based break-junction (STM-BJ) method to study transport through single-molecules comprising OP-relevant imine, imidazole, diazaborole, and boronate ester dynamic covalent chemical bridges. Notably, solution-stable boron-based compounds dissociate

The worldwide steady increase in the number of cancer patients motivates the development of innovative drug delivery systems for combination therapy as an effective clinical modality for cancer treatment. Here, we explored a design concept based on poly(ethylene glycol)

The total synthesis of the indole alkaloid (-)-andranginine has been achieved in 10 steps. Key reactions of the synthesis include a nucleophilic addition of acetylenyl anion to chiral

ConspectusEnantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

While chiral fused-ring tetrahydroisoquinoline (THIQ) and tetrahydro-β-carboline (THβC) scaffolds have attracted considerable interest due to their wide spectrum of biological activities, the synthesis of optically pure chiral fused-ring THIQs and THβCs remains a challenging task. Herein, a group of active imine reductases were identified to convert the imine precursors into the corresponding enantiocomplementary fused-ring THIQs and THβCs with high enantioselectivity and conversion, establishing an efficient and green chemoenzymatic approach to fused-ring alkaloids from 2-arylethylamines.

The Seebeck effect of a molecular junction in a hopping regime or tunneling-to-hopping transition remains uncertain. This paper describes the Seebeck effect in molecular epitaxy films (OPI

Singlet oxygen (

Omeprazole (OPZ) is a proton pump inhibitor commonly used for the treatment of gastric acid hypersecretion. Studies have revealed that use of OPZ can induce hepatotoxicity, but the mechanisms by which it induces liver injury are unclear. This study aimed to identify reactive metabolites of OPZ, determine the pathways of the metabolic activation, and define the correlation of the bioactivation with OPZ cytotoxicity. Quinone imine-derived glutathione (GSH)

β-Fluorinated amine is highly desirable for biological and pharmaceutical science, because replacing a C-H bond with a C-F bond can change the physical and chemical properties of the parent molecule to a large extent but not significantly alter its overall geometry. Herein, the highly stereoselective nucleophilic monofluoromethylation of imines have been developed. It is proposed that the chelated transition state enables the chiral induction by the dynamic kinetic resolution of the chiral α-fluoro carbanions.

We report the first covalent incorporation of reactive aliphatic amine species into covalent organic frameworks (COFs). This was achieved through the crystallization of an imine-linked COF, termed COF-609-Im, followed by conversion of its imine linkage to base-stable tetrahydroquinoline linkage through aza-Diels-Alder cycloaddition, and finally, the covalent incorporation of tris(3-aminopropyl)amine into the framework. The obtained COF-609 exhibits a 1360-fold increase in CO

Inspired by the discovery of a S═N bond in the collagen IV network and its essential role in stabilizing basement membranes, sulfilimines have drawn much attention in the fields of chemistry and biology. However, their further uptake is hindered by the lack of mild, efficient, and environmentally benign protocols by which sulfilimines can be constructed under biomolecule-compatible conditions. Here, we report a terminal oxidant-free copper-catalyzed dehydrogenative Chan-Lam coupling of free diaryl sulfilimines with arylboronic acids with excellent chemoselectivity and broad substrate compatibility. The mild reaction conditions and biomolecule-compatible nature allow the employment of this protocol in the late-stage functionalization of complex peptides, and more importantly, as an effective bioconjugation method as showcased in a model protein. A combined experimental and computational mechanistic investigation reveals that an inner-sphere electron-transfer process circumvents the sacrificial oxidant employed in traditional Chan-Lam coupling reactions. An energetically viable concerted pathway was located wherein a copper hydride facilitates hydrogen-atom abstraction from the isopropanol solvent to produce dihydrogen via a four-membered transition state.

The direct functionalization of Si−H bonds by the nitrene insertion methodology is described. A copper(I) complex bearing a trispyrazolylborate ligand catalyzes the transfer of a nitrene group from PhINTs to the Si−H bond of silanes, disilanes, and siloxanes, leading to the exclusive formation of Si−NH moieties in the first example of this transformation. The process tolerates other functionalities in the substrate such as several C−H bonds and alkyne and alkene moieties directly bonded to the silicon center. Density functional theory (DFT) calculations provide a mechanistic interpretation consisting of a Si−H homolytic cleavage and subsequent rebound to the Si-centered radical., We thank the Ministerio de Ciencia e Innovación for Grants PID2020-113797RB-C21, PID2020-112825RB-I00, and CEX2019-000925-S as well as FEDER for “Una manera de hacer Europa” funding. We also thank Junta de Andalucía (P20-00348) and Universidad de Huelva (P.O.Feder UHU202016). A.M.R. and R.P.-S. thank Ministerio de Universidades for the FPU fellowships (FPU17/02738 and FPU18/ 01138, respectively), and J.P.-R. thanks Fondo de Garantía Juvenil for a research contract. CERCA Programme/Generalitat de Catalunya is also acknowledged. We thank Prof. T. R. Belderrain for helpful discussions on 29Si NMR spectroscopy. Funding for open access charge: Universidad de Huelva / CBUA

Whereas triplet-nitrene complexes of the late transition metals are isolable and key intermediates in catalysis, singlet-nitrene ligands remain elusive. Herein we communicate three such palladium terminal imido complexes with singlet ground states. UV-vis-NIR electronic spectroscopy with broad bands up to 1400 nm as well as high-level computations (DFT, STEOM-CCSD, CASSCF/NEVPT2, EOS analysis) and reactivity studies suggest significant palladium(0) singlet-nitrene character. Although the aliphatic nitrene complexes proved to be too reactive for isolation in analytically pure form as a result of elimination of isobutylene, the aryl congener could be characterized by SC-XRD, elemental analysis, IR-, NMR spectroscopy, and HRMS. The complexes' distinguished ambiphilicity allows them to activate hexafluorobenzene, triphenylphosphine, and pinacol borane, catalytically dehydrogenate cyclohexene, and aminate ethylene via nitrene transfer at or below room temperature.

Emissions of NH

Sequential organocatalytic additions of 2-furanone and dihydroxyacetone derivatives to a crotonaldehyde lynchpin provide polyhydroxylated chains reminiscent of lactonized deoxo Kdn type sugars. Further homologation via Kulinkovich ring opening of the butyrolactone and acylation of the zinc homoenolate derived from the incipient cyclopropanol allows assembly of functionalized chain precursors to portimine. Our experiments probe the stability and reactivity of monosubstituted methylidene pyrrolines and generate advanced intermediates useful for exploring the biosynthesis and

By virtue of a fundamentally new reaction model of benzofuran-derived azadienes (BDAs), an unprecedented synthesis of biologically important pyrazoles has been achieved through a tandem [3 + 2] cycloaddition/ring-opening rearrangement reaction of BDAs with nitrile imines. The nature and type of substrates are found to act as a chemical switch to trigger two distinct reaction pathways. A minor modification to the substrates allows the access to spiro-pyrazolines.

Petroleum hydrocarbons are our major energy source and an important feedstock for the chemical industry. With the exception of combustion, the deep conversion of chemically inert hydrocarbons to more valuable chemicals is of considerable interest. However, two challenges hinder this conversion. One is the regioselective activation of inert carbon-hydrogen (C-H) bonds. The other is designing a pathway to realize this complicated conversion. In response to the two challenges, a multistep bioelectrocatalytic system was developed to realize the one-pot deep conversion from heptane to

Amphotericin B (AmB) is a highly hydrophobic drug with significant leishmanicidal activity whose use is limited by its poor water solubility and adverse effects. Polymer-drug conjugates are proposed as a delivery system designed to overcome those limitations while improving drug bioavailability, safety, and activity. Here, AmB was covalently linked to periodate-oxidized hyaluronic acid (HA) (oxidation degree of 30.1 ± 5.6%) via a Schiff base (HA-AmB imine). The conjugate presents high water solubility and self-assembles into particles with a mean size of 88.2 ± 17.6 nm, a negative charge (-28.3 ± 0.9 mV), and a drug content of 17.8 ± 1.4%. Spectroscopic studies revealed the presence of AmB in aggregate and super-aggregated forms in the conjugate, which could explain the significant reduction of the

Sulfonimidamides (SIAs) and sulfoximines (SOIs) have attracted attention due to their potential in agriculture and in medicinal chemistry as bioisosteres of biologically active compounds, and new synthetic methods are needed to access and explore these compounds. Herein, we present a light-promoted generation of perfluorinated aromatic nitrenes, from perfluorinated azides, that subsequently are allowed to react with sulfinamides and sulfoxides, generating achiral and chiral SIAs and SOIs. One of the enantiopure SIAs was evaluated as a novel chiral auxiliary in Grignard additions to the imines yielding the product in up to 96:4 diastereomeric ratio.

A new method for the synthesis of N-H imines from α-azidocarboxylic acids was developed, which proceeds through decarboxylative C-C bond cleavage catalyzed by a commercial diruthenium complex ([CpRu(CO)2]2) under visible light irradiation at room temperature within several minutes. The reactive products undergo condensation, which forms cyclic trimers (2,4,6-trialkylhexahydro-1,3,5-triazines) or linear N,N'-bis(arylmethylidene)arylmethanediamines in quantitative yields. Alternatively, the N-H imines can be trapped with benzylamine and 2-(aminomethyl)aniline, providing stable N-benylimines and tetrahydroquinazolines, respectively. Subsequent oxidation of tetrahydroquinazolines produced quinazolines.

Based on sequential organic transformations, that is, diimine formation, Staudinger [2 + 2] ketene-imine cycloaddition, and ring-closing metathesis (RCM) reactions, the synthesis with full structural identification including NMR and HRMS spectral data along with single X-ray diffraction analysis (for

A new type of diazo compounds, namely, CH-diazomethane sulfonamides (generated in situ from readily available α-acetyl-α-diazomethane sulfonamides), was employed in a 1,3-dipolar cycloaddition reaction with imines (also formed in situ from primary amines and aldehydes). The reaction gave hitherto undescribed 1,5-disubstituted 1,2,3-triazoline-4-sulfonamides, which were obtained in good to excellent yields with complete trans diastereoselectivity. These new sulfonamides based on the nonaromatic 1,2,3-triazoline core are rather attractive from a medicinal chemistry standpoint in light of the strong emphasis recently put on the nonflat, more saturated (higher Fsp3) scaffolds for lead-generation libraries. The oxidative aromatization of 1,2,3-triazoline-4-sulfonamides by manganese(IV) oxide gave nearly quantitative yields of 1,2,3-triazole-4-sulfonamides, of which only two examples have been reported in the literature.

Nonheme iron oxygenases utilize dioxygen to accomplish challenging chemical oxidations. A further understanding of the Fe-O2 intermediates implicated in these processes is challenged by their highly transient nature. To that end, we have developed a ligand platform featuring phosphinimide donors intended to stabilize oxidized, high-spin iron complexes. O2 exposure of single crystals of a three-coordinate Fe(II) complex of this framework allowed for in crystallo trapping of a terminally bound Fe-O2 complex suitable for XRD characterization. Spectroscopic and computational studies of this species support a high-spin Fe(III) center antiferromagnetically coupled to a superoxide ligand, similar to that proposed for numerous nonheme iron oxygenases. In addition to the apparent stability of this synthetic Fe-O2 complex, its ability to engage in a range of stoichiometric and catalytic oxidation processes demonstrates that this iron-phosphinimide system is primed for development in modeling oxidizing bioinorganic intermediates and green oxidation chemistry.

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three- and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.

Pinnatoxin G is a cyclic imine neurotoxin produced by dinoflagellates that has been reported in shellfish. Like other members of the pinnatoxin family, it has been shown to have its effects via antagonism of the nicotinic acetylcholine receptors, with preferential binding to the α7 subunit often upregulated in cancer. Because increased activity of α7 nicotinic acetylcholine receptors contributes to increased growth and resistance to apoptosis, the effect of pinnatoxin G on cancer cell viability was tested. In a panel of six cancer cell lines, all cell types lost viability, but HT29 colon cancer and LN18 and U373 glioma cell lines were more sensitive than MDA-MB-231 breast cancer cells, PC3 prostate cancer cells, and U87 glioma cells, correlating with expression levels of α7, α4, and α9 nicotinic acetylcholine receptors. Some loss of cell viability could be attributed to cell cycle arrest, but significant levels of classical apoptosis were found, characterized by caspase activity, phosphatidylserine exposure, mitochondrial membrane permeability, and fragmented DNA. Intracellular Ca2+ levels also dropped immediately upon pinnatoxin G treatment, which may relate to antagonism of nicotinic acetylcholine receptor-mediated Ca2+ inflow. In conclusion, pinnatoxin G can decrease cancer cell viability, with both cytostatic and cytotoxic effects.

To avoid excessive usage of antibiotics and antimicrobial agents, smart wound dressings permitting controlled drug release for treatment of bacterial infections are highly desired. In search of a sensitive stimulus to activate drug release under physiological conditions, we found that the glass transition temperature (

Recently, many studies have been reported on functional adhesives that are applicable in wet conditions as well as in air conditions. In this study, a novel polymer hydrogel that mimics the mussel foot proteins (Mfps) was designed as an adhesive that can adhere strongly to various substrates in wet conditions. Polyallylamine-hydrocaffeic acid (PAA-CA) conjugates were synthesized to introduce the catechol moiety into the PAA backbone. The PAA-CA hydrogels were simply prepared by controlling the pH to enable the formation of a dynamic imine bond via the Schiff base reaction without any additional cross-linking agents. Owing to its residual amino groups, the PAA-CA hydrogel showed improved adhesive strength in wet conditions, which was found to be ∼4.7 times higher than in dry conditions. In addition, dual-cross-linked PAA-CA hydrogels were prepared by the addition of laponite (LP). The synergistic effect of the dynamic imine bonds and ionic bonds of the PAA-CA/LP nanocomposite hydrogels led to improved mechanical and self-healing properties. PAA-based hydrogels have great potential for more diverse applications than those of the commercial adhesives.

Chiral 1,2-diamino compounds are important building blocks in organic chemistry for biological applications and as asymmetric inducers in stereoselective synthesis that are challenging to prepare in a straightforward and stereoselective manner. Herein, we disclose a cost-effective and readily available Cu-catalyzed system for the reductive coupling of a chiral allenamide with N-alkyl substituted aldimines to access chiral 1,2-diamino synthons as single stereoisomers in high yields. The method shows broad reaction scope and high diastereoselectivity and can be easily scaled using standard Schlenk techniques. Mechanistic investigations by density functional theory calculations identified the mechanism and origin of stereoselectivity. In particular, the addition to the imine was shown to be reversible, which has implications toward development of catalyst-controlled stereoselective variants of the identified reductive coupling of imines and allenamides.

Prodrug-type polymer-drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE

A general procedure for the asymmetric synthesis of highly substituted 1,2-amino alcohols in high yield and diastereoselectivity is described that uses organometallic additions of a wide range of nucleophiles to

Condensation of imines with anhydrides have been proven to be a valuable method for the synthesis of tetrahydroisoquinolones. Herein, we report the application of this chemistry with DNA-conjugated imines. Condensation of DNA-conjugated imine (which can be formed in situ from DNA-conjugated amines and aldehydes or DNA-conjugated aldehyde and primary amines) with homophthalic anhydride produces isoquinolones in moderate to excellent yields. The formed isoquinolone can be further derivatized with a variety of amines through amide bond formation. Development of this chemistry on-DNA enables the synthesis of an isoquinolone core-focused DNA-encoded library.

A Rh(III)-catalyzed synthesis of bicyclic [1,3,5]triazinones from a diverse array of imines coupled with ethyl (pivaloyloxy)carbamate is reported. The preparation of [5,6]- and [6,6]-bicyclic heterocycles substituted with aryl, alkyl, and alkoxy groups demonstrated a broad reaction scope. The efficiency of this approach was further enhanced with the development of a three-component variant featuring in situ imine formation. X-ray crystallographic characterization of a rhodacycle formed by imidoyl C-H activation provides support for the proposed mechanism.

Nanoscale imine-linked covalent organic frameworks (nCOFs) were first loaded with the anticancer drug Doxorubicin (Dox), coated with magnetic iron oxide nanoparticles (γ-Fe2O3 NPs), and stabilized with a shell of poly(l-lysine) cationic polymer (PLL) for simultaneous synergistic thermo-chemotherapy treatment and MRI imaging. The pH responsivity of the resulting nanoagents (γ-SD/PLL) allowed the release of the drug selectively within the acidic microenvironment of late endosomes and lysosomes of cancer cells (pH 5.4) and not in physiological conditions (pH 7.4). γ-SD/PLL could efficiently generate high heat (48 °C) upon exposure to an alternating magnetic field due to the nCOF porous structure that facilitates the heat conduction, making γ-SD/PLL excellent heat mediators in an aqueous solution. The drug-loaded magnetic nCOF composites were cytotoxic due to the synergistic toxicity of Dox and the effects of hyperthermia in vitro on glioblastoma U251-MG cells and in vivo on zebrafish embryos, but they were not significantly toxic to noncancerous cells (HEK293). To the best of our knowledge, this is the first report of multimodal MRI probe and chemo-thermotherapeutic magnetic nCOF composites.

Regression modeling is becoming increasingly prevalent in organic chemistry as a tool for reaction outcome prediction and mechanistic interrogation. Frequently, to acquire the requisite amount of data for such studies, researchers employ combinatorial datasets to maximize the number of data points while limiting the number of discrete chemical entities required. An often-overlooked problem in modeling studies using combinatorial datasets is the tendency to fit on patterns in the datasets (i.e., the presence or absence of a reactant or catalyst) rather than to identify meaningful trends between descriptors and the response variable. Consequently, the generality and interpretability of such models suffer. This report illustrates these well-known pitfalls in a case study, demonstrates the necessary control experiments to identify when this property will be problematic, and suggests how to perform further validation to assess general applicability and interpretability of models trained using combinatorial datasets.

Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-(N-butylethanimidoyl)ethyl)-4-hydroxy-2H-chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure–activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC(50))

Sulfoximines have been largely disregarded in medicinal chemistry for a long time. However, recently, they have risen to the apparent level of stardom on the drug discovery scene. Considering the outstanding properties of sulfoximines, this versatile functional group has advanced to implementation in several drug discovery programs. Currently, this fashionable functional group can be found in various hit-to-lead and lead optimization studies in early stages and in several compounds currently in clinical trials. Herein, we review recent developments to demonstrate the scope and limitations of this interesting and versatile functional group in medicinal chemistry and drug discovery.

The mechanism of the organocatalytic Cope rearrangement is elucidated through a combined computational and experimental approach. As reported previously, hydrazides catalyze the Cope rearrangement of 1,5-hexadiene-2-carboxaldehydes via iminium ion formation, and seven- and eight-membered ring catalysts are more active than smaller ring sizes. In the present work, quantum mechanical computations and kinetic isotope effect experiments demonstrate that the Cope rearrangement step, rather than iminium formation, is rate-limiting. The computations further explain how the hydrazide catalyst lowers the free-energy barrier of the Cope rearrangement via an associative transition state that is stabilized by enehydrazine character. The computations also explain the catalyst ring size effect, as larger hydrazide rings are able to accommodate optimal transition-state geometries that minimize the unfavorable lone-pair repulsion between neighboring nitrogen atoms and maximize the favorable hyperconjugative donation from each nitrogen atom into neighboring electron-poor sigma bonds, with the seven-membered catalyst achieving a nearly ideal transition-state geometry that is comparable to that of an unconstrained acyclic catalyst. Experimental kinetics studies support the computations, showing that the seven-membered and acyclic hydrazide catalysts react 10 times faster than the six-membered catalyst. Unraveling the mechanism of this reaction is an important step in understanding other reactions catalyzed by hydrazides, and explaining the ring size effect is critical because cyclic catalysts provide a constrained scaffold, enabling the development of asymmetric variants of these reactions.

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach. The synthetic procedure reported herein represents a cleaner route toward thiazolidine-2-imines as compared to traditional methodologies. Moreover, the biological significance of combinatorially synthesized thiazolidin-2-imines has been investigated for their use as possible inhibitors for acetyl cholinesterase through molecular docking studies.

Electron paramagnetic resonance (EPR) studies of the rhenium(II) complex Re(η5-Cp)(BDI) (1; BDI = N,N′-bis(2,6-diisopropylphenyl)-3,5-dimethyl-β-diketiminate) have revealed that this species revers...

Ugi four-component reactions (U-4CRs) are widely recognized as being highly efficient for the synthesis of pseudopeptides. However, the products of these reactions are not so interesting as drug candidates because they are not conformationally restricted enough for a potent interaction with biological targets. One possible way to overcome this problem is to replace amine and oxo components in the U-4CRs with cyclic imines in so-called Joullie-Ugi three-component reactions (JU-3CRs). This approach provides a robust single-step route to peptide moieties connected to N-heterocyclic motifs that are found as core skeletons in many natural products and pharmaceutical compounds. JU-3CRs also provide much better diastereoselectivity than their four-component analogues. We survey here the redesign of many synthetic routes for the efficient preparation of a wide variety of three-, five-, six-, and seven-membered heterocyclic compounds connected to the peptide backbone. Additionally, in the Ugi reactions based on the cyclic imines, α-acidic isocyanides, or azides can be replaced with normal isocyanides or acids, respectively, leading to the synthesis of N-heterocycles attached to oxazoles or tetrazoles, which are of great pharmaceutical significance. This Review includes all research articles related to Ugi reactions based on the cyclic imines to the year 2020 and will be useful to chemists in designing novel synthetic routes for the synthesis of individual and combinatorial libraries of natural products and drug-like compounds.

There is a growing demand for antibacterial materials around the world in recent years because they can be used for preventing pathogen infection, which is one of the major threats to human health. However, the mechanical damage of the antibacterial materials may weaken their protective effect since bacteria can invade through the cracks of the material. Therefore, antibacterial materials with self-healing ability, in which the mechanical damage can be spontaneously healed, exhibit better reliability and a longer lifespan. In this article, we prepared a series of low-cost antibacterial polymer blends and polymer/small molecule blend materials with excellent self-healing ability and high mechanical strength by a one-pot reaction under mild conditions. These materials were facilely obtained by blending a tiny amount of commercialized cationic antibacterial chemicals, poly(ethylene imine) (PEI) or cetyltrimethylammonium bromide (CTAB), into a self-healing, mechanically robust polymer, poly(ether-thioureas) (PETU). It can be found that they can effectively kill

Chitosan is a polysaccharide widely used as a structuring agent in foods and other materials because of its positive charge (amino groups). At present, however, it is difficult to form and stabilize emulsions using chitosan due to its high hydrophilicity. In this study, oil-in-water emulsions were prepared using a one-pot green-chemistry method. The chitosan and aldehyde molecules were in situ interfacially conjugated during homogenization, which promoted the adsorption of chitosan onto the oil droplet surfaces where they created a protective coating. The universality of this method was verified by using chitosan with different molecular weights and four kinds of natural aldehydes [cinnamaldehyde (CA), citral (CT), citronella (CN), and vanillin (VL)]. Chitosan with higher molecular weight facilitated the formation of emulsions. By harnessing the dynamic covalent nature of imine bonds, chitosan emulsions with an imine link display dynamic behavior with acid-catalyzed hydrolysis. The aldehyde structure could control the pH point of trigger for breakdown of emulsions, which was 1.0, 3.0, 4.0, and 4.0 for CA emulsion, CT emulsion, CN emulsion, and VL emulsion, respectively. At pH 6.5, aldehyde helped to decrease the interfacial tension of chitosan to about 10 mN/m, while this value would increase if the pH decreased by adding acid during the measurement. Chemical kinetics studies indicated that the hydrophobicity and conjugation effect of the aldehyde together determined the trigger points and properties of the emulsion. Finally, we used the optimized emulsions to encapsulate and control the release of curcumin. The gastric release behavior of the curcumin depended on aldehyde structure: VL > CN > CT ≈ CA. Hence, a tailor-made trigger release emulsion system can be achieved by rational selection and design of aldehyde structure to control hydrophobicity and conjugation effect of aldehydes.

Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably, we achieved successive β-functionalization and oxidation of amino acid Schiff bases to afford dehydroalanine derivatives bearing tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiff base, alkyl bromides, and styrene derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,β-continuous tetrasubstituted carbon. The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.