Canagliflozin alleviates pulmonary hypertension by activating PPARγ and inhibiting its S225 phosphorylation.

Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.

Unraveling the Chemistry of High Valent Arylcopper Compounds and Their Roles in Copper-Catalyzed Arene C-H Bond Transformations Using Synthetic Macrocycles.

Recent decades have witnessed a resurgence of the study of copper-catalyzed organic reactions. As the surrogate of noble metal catalysts, copper salts have been shown to exhibit remarkable versatility in activating various C-H bonds enabling the construction of diverse carbon-carbon and carbon-heteroatom bonds. Advantageously, copper salts are also naturally abundant, inexpensive, and less toxic in comparison to precious metals. Despite significant developments in synthesis, the mechanism of copper catalysis remains elusive. Hypothetical pathways such as the two-electron Cu(III)/Cu(I) and Cu(II)/Cu(0) catalytic cycles and the one-electron Cu(II)/Cu(I) catalytic cycle have been invoked to diagram C-H bond transformations because of the formidable challenges to isolate and characterize transient high valent organocopper intermediates. In fact, organocopper chemistry has been dominated for a long time by the acknowledged nucleophilic organocopper(I) compounds. Since the beginning of the new millennium, we have been systematically studying the supramolecular chemistry of heteracalix[n]aromatics. Owing to the ease of their synthesis and selective functionalizations, self-tunable conformation and cavity structures resulting from the interplay of heteroatoms with aromatic subunits, and outstanding properties in molecular recognition and self-assembly, heteracalix[n]aromatics have become a class of privileged synthetic macrocyclic hosts. Our journey to the chemistry of high valent organocopper compounds started with a serendipitous discovery of the facile formation of a stable organocopper compound, which contains astonishingly a Ph-Cu(III) σ-bond under very mild aerobic conditions. When we examined routinely the effect of the macrocyclic structures on noncovalent complexation properties, titration of tetraazacalix[1]arene[3]pyridine with Cu(ClO4)2·6H2O resulted in the precipitation of dark-purple crystals of phenylcopper(III) diperchlorate. Our curiosity about the transformation of an arene C-H bond into an Ar-Cu(III) bond prompted us to conduct an in-depth investigation of the reaction of macrocyclic arenes with copper(II) salts, leading to the isolation of arylcopper(II) compounds which are unprecedented and the missing link in organocopper chemistry. With structurally well-defined organometallics in hand, we have explored extensively the reactivities of both arylcopper(II) and arylcopper(III) compounds, demonstrating their versatility and uniqueness in chemical synthesis. Novel and fascinating arene C-H transformations under copper catalysis have been developed. Using acquired high valent arylcopper compounds as molecular probes, and employing the functionalizations of tetraazacalix[1]arene[3]pyridines as model reactions, we have revealed the diverse mechanisms of copper-promoted arene C-H bond reactions. Elusive reaction pathways of some copper-catalyzed C-X bond activations have also been unraveled. In the meantime, we have also witnessed pleasingly the rapid development of field with the advent of new high valent organocopper compounds. Without any doubt, studies of the synthesis, reactivity, and catalysis of high valent organocopper compounds have been reshaping the field of organocopper chemistry. This Account summarizes our endeavors to explore the chemistry of structurally well-defined arylcopper(II) and arylcopper(III) compounds and the mechanisms of copper-catalyzed arene C-H and C-X bond transformations. We hope this Account will inspire chemists to study thoroughly the fundamentals and the cutting-edge catalysis of high valent organocopper compounds advancing and redefining the discipline of organocopper chemistry.

Functionalized Hydrocarbon Belts: Synthesis, Structure and Properties.

Hydrocarbon belts have drawn great attention because of their unique structures and tantalizing properties. Although a few belts and heteroatom-doped analogs have been synthesized, belt molecules containing non-hexagonal rings remain rare. Herein we report the construction and application of unprecedented zigzag-type hydrocarbon belts which contain functionalized eight-membered rings. The synthesis features fourfold intramolecular acylation reactions of resorcin[4]arene-derived intermediates, which affords C4 -symmetric tetrabenzobelt[4]arene[4]cyclooctatrienones. Stereoselective ketone reduction with LiAlH4 and nucleophilic addition with alkynyllithiums provide the corresponding tetrahydroxylated belts. The tetraol and its methyl ether are powerful and selective hosts to form 2 : 1 and 1 : 1 complexes with cesium ion, respectively, with binding constants up to (1.71±0.33)×1011  M-2 and (1.50±0.16)×106  M-1 . In addition, enantiopure C4 -symmetric belts can emit CPL with |glum | being around 0.01.

Highly Strained Oxygen-Doped Chiral Molecular Belts of the Zigzag-Type with Strong Circularly Polarized Luminescence.

Herein we report a two-directional cyclization strategy for the synthesis of highly strained depth-expanded oxygen-doped chiral molecular belts of the zigzag-type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3-dihydro-1H-phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring-closing olefin metathesis reactions furnished a highly strained O-doped C2 -symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (µ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum | up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt-derived chiroptical materials with high CPL activities.

Thiazole Boron Difluoride Dyes with Large Stokes Shift, Solid State Emission and Room-Temperature Phosphorescence.

The small Stokes shift and weak emission in the solid state are two main shortcomings associated with the boron-dipyrromethene (BODIPY) family of dyes. This study presents the design, synthesis and luminescent properties of boron difluoro complexes of 2-aryl-5-alkylamino-4-alkylaminocarbonylthiazoles. These dyes display Stokes shifts (Δλ, 77-101 nm) with quantum yields (ϕFL ) up to 64.9 and 34.7 % in toluene solution and in solid state, respectively. Some of these compounds exhibit dual fluorescence and room-temperature phosphorescence (RTP) emission properties with modulable phosphorescence quantum yields (ϕPL ) and lifetime (τp up to 251 µs). The presence of intramolecular H-bonds and negligible π-π stacking revealed by X-ray crystal structure might account for the observed large Stokes shift and significant solid-state emission of these fluorophores, while the enhanced spin-orbit coupling (SOC) of iodine and the self-assembly driven by halogen bonding, π-π and C-H… π interactions could be responsible for the observed RTP of iodine containing phosphors.

Toward the Synthesis of a Highly Strained Hydrocarbon Belt.

Hydrocarbon belts including fully conjugated beltarenes and their (partially) saturated analogs have fascinated chemists for decades due to their aesthetic structures, tantalizing properties, and potential applications in supramolecular chemistry and carbon nanoscience and nanotechnology. However, synthesis of hydrocarbon belts still remains a formidable challenge. We report in this communication a general approach to hydrocarbon belts and their derivatives. Closing up all four fjords of resorcin[4]arene derivatives through multiple intramolecular Friedel-Crafts alkylation reactions in an operationally simple one-pot reaction manner enabled efficient construction of octohydrobelt[8]arenes. Synthesis of belt[8]arene from DDQ-oxidized aromatization of octohydrobelt[8]arene under different conditions resulted in aromatization and simultaneous [4 + 2] cycloaddition reactions with DDQ or TCNE to produce selectively tetrahydrobelt[8]arene-DDQ2, tetrahydrobelt[8]arene-TCNE2, and belt[8]arene-DDQ4 adducts. Formation of belt[8]arene, a fully conjugated hydrocarbon belt, was observed from retro-Diels-Alder reaction of a belt[8]arene-DDQ4 adduct with laser irradiation under MALDI conditions. The new and practical synthetic method established would open an avenue to create belt-shaped molecules from easily available starting materials.

Hydrocarbon Belts with Truncated Cone Structures.

We report in this communication the synthesis, structure, and application of a novel type of hydrocarbon belts. Starting from inexpensive and easily available resorcin[n]arenes, a closing-all-fjords strategy featuring exhaustive triflation of phenolic hydroxyl groups followed by consecutively the transition-metal-catalyzed vinylation and intramolecular olefin metathesis allowed facile construction of belt[n]arene[n]tropilidenes (n = 4, 6), which adopt double-stranded macrocyclic belt structures with unique truncated cone cavities. Selective hydrogenation reactions of olefin and benzene subunits led to diverse hydrocarbon belts with varied structures. Moreover, the resulting molecular belts acted as synthetic host materials to include selectively small molecules such as nitromethane and p-xylene.

Catalytic Enantioselective Synthesis and Switchable Chiroptical Property of Inherently Chiral Macrocycles.

We report herein a strategy to construct enantiopure inherently chiral macrocycles, ABCD-type heteracalix[4]aromatics, through a catalytic enantioselective intramolecular C-N bond forming reaction. A chiral ligand-palladium complex was found to efficiently induce the inherent chirality of molecules during the macrocyclization process with ee values up to >99%. The resulting ABCD-type heteracalix[4]aromatics displayed excellent and pH-triggered switchable electronic circular dichroism and circularly polarized luminescence properties.

Fused N-Heterocycles with Contiguous Stereogenic Centers Accessed by an Asymmetric Catalytic Cascade Reaction of Tertiary Enamides.

We report in this article a cascade reaction strategy for the synthesis of complex N-heterocyclic compounds with contiguous and tetrasubstituted stereogenic carbons. Under the sequential catalysis of a chiral binol-Ti complex and BF3 , cyclopentanone-derived tertiary enamides undergo an enantioselective enamine addition to ketone carbonyls followed by diastereoselective trapping of the resulting acyliminiums by electron-rich aryl moieties to furnish four- and five-membered ring-fused N-heterocyclic products as the sole diastereomers in high yields with up to 99 % ee.

Construction of the Erythrinane Core Skeleton via Asymmetric Catalytic Cascade Reaction of Tertiary Enamides.

We report herein an efficient cascade strategy for the rapid construction of a highly enantioenriched erythrinane core skeleton. Under the sequential catalysis of a chiral Cr(III)(salen)Cl and InCl3, cyclohexanone-derived tertiary enamides undergo an intramolecular enantioselective nucleophilic addition followed by diastereoselective Pictet-Spengler cyclization. This method is highly enantio- and diastereoselective, leading to diverse erythrina alkaloid derivatives as the sole diastereoisomer with up to 98% ee.

Synthesis and Structure of Functionalized Zigzag Hydrocarbon Belts.

Described in this paper are the synthesis and structure of novel and edge-functionalized zigzag hydrocarbon belts. A stepwise "fjord-stitching" strategy featuring repetitive intramolecular acylation reactions of a resorcin[4]arene derivative as the key steps afforded a biscarbonyl-functionalized octahydrobelt[8]arene product. Facile ketone reduction with NaBH4 and nucleophilic addition with n-butyllithium produced secondary and tertiary alcohol-containing molecular belts, respectively. Selective oxidation reactions of biscarbonyl-bearing octahydrobelt[8]arene with m-CPBA and (PhSeO)2 O furnished the corresponding lactone- and 1,4-quinone-embedded molecular belts. Depending on the functional groups on the edges, the acquired belt molecules adopt different shapes such as square prism, truncated cone, and elliptical cylinder.

Synthesis of i-Corona[6]arenes for Selective Anion Binding: Interdependent and Synergistic Anion-π and Hydrogen-Bond Interactions.

i-Corona[3]arene[3]tetrazines were synthesized from the nucleophilic aromatic substitution reaction of resorcinol and its derivatives with 3,6-dichlorotetrazine in a one-pot fashion under mild conditions. All of the resulting macrocycles adopted 1,3,5-alternate conformation irrespective of the nature of the substituents on both upper- and lower-rims. i-Corona[3]arene[3]tetrazine was found to self-regulate its macrocyclic conformation and cavity to recognize anions with binding constants spanning from 26 M-1 to 2.2×103  M-1 depending on the structure of the anions. The selective binding resulted from a significant interdependent and synergistic effect between multiple tetrazine π/anion and Caryl -H/anion hydrogen bond interactions. Taking advantage of synergistic effect revealed, a cyanobenzene-embedded i-corona[3]arene[3]tetrazine was designedly synthesized and highly selective and very strong affinity toward nitrate with a binding constant of 2.2×105  M-1 was achieved.

Construction of Hydrocarbon Nanobelts.

Linearly fused hydrocarbon nanobelts are a unique type of double-stranded macrocycles that would serve as not only the powerful hosts in supramolecular science but also the templates to grow zig-zag carbon nanotubes with defined diameters. Fully conjugated hydrocarbon nanobelts such as belt[n]arenes would also possess unique physical and chemical properties. Despite the importance, both fully conjugated and (partially) saturated hydrocarbon nanobelts remain largely unexplored because of the lack of cyclization methods. Reported here is the construction of nanometer sized H12 -belt[12]arenes based on the strategy to close up all fjords of resorcin[6]arene by means of six-fold intramolecular alkylation reactions of resorcin[6]arene derivatives. All resulting H12 -belt[12]arenes produce a very similar nanobelt core structure with six benzene rings and six boat 1,4-cyclohexadiene rings being alternately linear-fused to give a nearly equilateral hexagonal cylinder. The average long diagonal is around 1 nm and the height of the cylinder is about 0.3 nm. The acquired H12 -belt[12]arenes would be the potential precursors to various hydrocarbon nanobelts including fully conjugated belt[12]arenes.

Synthesis of Electron-Deficient Corona[5]arenes and Their Selective Complexation with Dihydrogen Phosphate: Cooperative Effects of Anion-π Interactions.

Reported here are the syntheses, conformational structures, electrochemical properties, and noncovalent anion binding of corona[5]arenes. A (3+2) fragment coupling reaction proceeded efficiently under mild reaction conditions to produce a number of novel heteroatom- and methylene-bridged corona[3]arene[2]tetrazine macrocycles. Selective oxidation of the sulfur atom between two phenylene rings afforded sulfoxide- and sulfone-linked corona[5]arenes in good yields. All corona[5]arenes synthesized adopted similar 1,2,4-alternate conformational structures, forming pentagonal cavities. The cavity sizes and the electronic properties such as redox potentials, were measured with CV and DPV, and were influenced by the different bridging units. As electron-deficient macrocycles, the acquired corona[3]arene[2]tetrazines served as highly selective hosts, forming complexes with the hydrogen-bonded dimer of dihydrogen phosphate through cooperative anion-π interactions.

Oxygen- and Nitrogen-Embedded Zigzag Hydrocarbon Belts.

Despite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom-embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N-doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular SN Ar and palladium-catalyzed intermolecular C-N bond formation reactions. Preorganized conformations of mono-macrocyclic, half-belt and quasi-belt compounds were revealed to facilitate cyclization reactions to construct heteroatom-linked octahydrobelt[8]arenes. The acquired products had strained square-prism-shaped belt structures in which all six-membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom-bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.

Radical Reactivity, Catalysis, and Reaction Mechanism of Arylcopper(II) Compounds: The Missing Link in Organocopper Chemistry.

Organocopper(I) compounds are recognized as carbon nucleophiles, while organocopper(III) complexes are involved in copper catalysis as intermediates to undergo a cross-coupling reaction with various anionic nucleophiles. In contrast to the chemistry of organocopper(I) and (III) compounds, organocopper(II) chemistry is virtually a missing link in integral organocopper chemistry because structurally well-defined organocopper(II) compounds have barely been isolated or studied. We report in this Article an investigation of the radical reactions of stable and structurally well-defined arylcopper(II) compounds, obtained readily from the arene C-H bond reaction of macrocyclic azacalix[1]arene[3]pyridines and Cu(ClO4)2. We have found that arylcopper(II) compounds acted as essentially radical species to undergo an efficient three-component reaction with radical initiators 2,2'-azobis(isobutyronitrile) (AIBN) or 2,2'-azobis(2,4-dimethylvaleronitrile) (ABVN) and α,ß-unsaturated compounds CH2═CHX (X = CO2CH3, CN, CONH2, COCH3, and SO2Ph) to afford polyfunctionalized products. Combined experimental and theoretical studies revealed that radicals couple directly with the Caryl atom of arylcopper(II) compounds to form Calkyl-Caryl bonds through a Cu(II)/Cu(I) mechanism. Comprehension of the formation and radical reactivity of arylcopper(II) compounds has allowed the development of a copper-catalyzed three-component radical reaction for arene C-H bond functionalization.

Intramolecular Arylation of Tertiary Enamides through Pd(OAc)2-Catalyzed Dehydrogenative Cross-Coupling Reaction: Construction of Fused N-Heterocyclic Scaffolds and Synthesis of Isoindolobenzazepine Alkaloids.

Pd(OAc)2-catalyzed intramolecular dehydrogenative cross-coupling reaction between tertiary enamides, which were derived from the condensation of 2-arylethylamines and methyl o-acetylbenzoate, and arenes enabled synthesis of 7,8-dihydro-5 H-benzo[4,5]azepino[2,1- a]isoindol-5-one derivatives under mild conditions. The synthetic method was applied in the total synthesis of aporhoeadane alkaloids palmanine, lennoxamine, and chilenamine in only three or four steps.

Silver-Catalyzed Three-Component 1,1-Aminoacylation of Homopropargylamines: α-Additions for Both Terminal Alkynes and Isocyanides.

The reaction of secondary homopropargylamines, isocyanides, and water in the presence of a catalytic amount of silver acetate and subsequent purification by chromatography on silica gel afforded substituted proline amides in good to excellent yields. Primary homopropargylamines underwent a cyclizative Ugi-Joullié three-component reaction with isocyanides and carboxylic acids to afford functionalized N-acyl proline amides. High diastereoselectivity was observed in the synthesis of 4-alkoxy and 4,5-disubstituted proline derivatives. This work represents the first examples of a three-component cyclizative 1,1-aminoacylation of terminal alkynes.

Fluorophores for Excited-State Intramolecular Proton Transfer by an Yttrium Triflate Catalyzed Reaction of Isocyanides with Thiocarboxylic Acids.

Discovery of new chemical reactivity of a given functional group can often result in innovative synthesis of important chemical entities that possess unprecedented properties. We designed and developed a one-step synthesis of 5-amino-4-carboxamidothiazoles 1 by an yttrium-triflate-catalyzed reaction of thiocarboxylic acids 2 with isocyanides 3. In this reaction, both reactants 2 and 3 deviated from their normal reactivities because of metal coordination. The resulting heterocycles are novel prototypical structures for the double ESIPT process. Some of them were excited by visible light irradiation and emitted fluorescence at the NIR region with large Stokes shift, high quantum yield, and strong solvatochromism.

Catalytic Enantioselective Double Carbopalladation/C-H Functionalization with Statistical Amplification of Product Enantiopurity: A Convertible Linker Approach.

Combining a catalytic enantioselective reaction with dimerization in a single operation is an efficient way to upgrade the enantiomeric excesses (ee) of the product. Palladium-catalyzed reaction of N-(2-iodophenyl)-N-methyl methacrylamide derivatives with oxadiazole afforded, by a double enantioselective carbopalladation/intermolecular heteroarene C-H alkylation sequence, homodimers in good yields with excellent ee values. The dimer was subsequently elaborated to the monomer in which the linker (oxadiazole) was incorporated into the target product.