Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of ß-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of ß-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of ß-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral ß-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Rh(III)-Catalyzed Diastereo- and Enantioselective Regiodivergent (Hetero)Arylamidation of (Homo)Allylic Sulfides.

A rhodium-catalyzed 3-component conjunctive diastereo- and regioselective arylamidation of (homo)allylic sulfides, organon boronic acids, and dioxazolones is reported. These reactions deliver the 1,2-insertion and 2,1-insertion arylamidation products, respectively, for allylic sulfides and homoallylic sulfides. The enantioselective arylamidation of terminal and internal allylic sulfides is achieved, furnishing various 1,3-N,S compounds featuring one or two contiguous stereocenters in high yields and with high diastereo- and enantioselectivities. Mechanistic studies suggest a change in the turnover-limiting and selectivity-determining steps induced by the native and easily removable sulfide group.

Recent advances in Rh(I)-catalyzed enantioselective C-H functionalization.

Chiral carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds are pervasive and very essential in natural products, bioactive molecules, and functional materials, and their catalytic construction has emerged as one of the hottest research fields in synthetic organic chemistry. The last decade has witnessed vigorous progress in Rh(I)-catalyzed asymmetric C-H functionalization as a complement to Rh(II) and Rh(III) catalysis. This review aims to provide the most comprehensive and up-to-date summary covering the recent advances in Rh(I)-catalyzed C-H activation for asymmetric functionalization. In addition to the development of diverse reactions, chiral ligand design and mechanistic investigation (inner-sphere mechanism, outer-sphere mechanism, and 1,4-Rh migration) will also be highlighted.

Asymmetric Hydrogenation of Racemic 2-Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers.

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural ß-amino acids via facile debenzylation and amino alcohol upon reduction.

Chiral Cpx Rhodium(III)-Catalyzed Enantioselective Aziridination of Unactivated Terminal Alkenes.

Chiral cyclopentadienyl-rhodium(III) Cpx Rh(III) catalysis has been demonstrated to be competent for catalyzing highly enantioselective aziridination of challenging unactivated terminal alkenes and nitrene sources. The chiral Cpx Rh(III) catalysis system exhibited outstanding catalytic performance and wide functional group tolerance, yielding synthetically important and highly valuable chiral aziridines with good to excellent yields and enantioselectivities (up to 99 % yield, 93 % ee). This protocol presents a novel and effective strategy for synthesizing enantioenriched aziridines from simple alkenes. Various transformations were performed on the aziridine products, illustrating the versatility and synthetic potential of this protocol for constructing highly functionalized compounds.

Photocatalytic enantioselective Minisci reaction of ß-carbolines and application to natural product synthesis.

A highly efficient enantioselective direct C-H functionalization of ß-carbolines via a Minisci-type radical process under a photo-redox and chiral phosphoric acid cooperative catalytic system has been disclosed. Through this protocol, a wide range of C1 aminoalkylated ß-carbolines were constructed directly with high levels of enantioselectivities from readily available ß-carbolines and alanine-derived redox-active esters. This transformation allows straightforward access to highly valuable enantioenriched ß-carbolines, which are an intriguing structural motif in valuable natural products and synthetic bio-active compounds. This protocol has been utilized as a highly efficient synthetic strategy for the concise asymmetric total synthesis of marine alkaloids eudistomin X, (+)-eudistomidin B and (+)-eudistomidin I.

Enantioselective Hydroxylation of Dihydrosilanes to Si-Chiral Silanols Catalyzed by In Situ Generated Copper(II) Species.

Catalytic enantioselective hydroxylation of prochiral dihydrosilanes with water is expected to be a highly efficient way to access Si-chiral silanols, yet has remained unknown up to date. Herein, we describe a strategy for realizing this reaction: using an alkyl bromide as a single-electron transfer (SET) oxidant for invoking CuII species and chiral multidentate anionic N,N,P-ligands for effective enantiocontrol. The reaction readily provides a broad range of Si-chiral silanols with high enantioselectivity and excellent functional group compatibility. In addition, we manifest the synthetic potential by establishing two synthetic schemes for transforming the obtained products into Si-chiral compounds with high structural diversity. Our preliminary mechanistic studies support a mechanism involving SET for recruiting chiral CuII species as the active catalyst and its subsequent σ-metathesis with dihydrosilanes.

Direct reductive amination of ketones with ammonium salt catalysed by Cp*Ir(III) complexes bearing an amidato ligand.

A series of half-sandwich Ir(III) complexes 1-6 bearing an amidato bidentate ligand were conveniently synthesized and applied to the catalytic Leuckart-Wallach reaction to produce racemic α-chiral primary amines. With 0.1 mol% of complex 1, a broad range of ketones, including aryl ketones, dialkyl ketones, cyclic ketones, α-keto acids, α-keto esters and diketones, could be transformed to their corresponding primary amines with moderate to excellent yields (40%-95%). Asymmetric transformation was also attempted with chiral Ir complexes 3-6, and 16% ee of the desired primary amine was obtained. Despite the unsatisfactory enantio-control achieved so far, the current exploration might stimulate more efforts towards the discovery of better chiral catalysts for this challenging but important transformation.

Mechanistic Insights into Formation of All-Carbon Quaternary Centers via Scandium-Catalyzed C-H Alkylation of Imidazoles with 1,1-Disubstituted Alkenes.

This density functional theory (DFT) study reveals a detailed plausible mechanism for the Sc-catalyzed C-H cycloaddition of imidazoles to 1,1-disubstituted alkenes to form all-carbon quaternary stereocenters. The Sc complex binds the imidazole substrate to enable deprotonative C2-H bond activation by the Sc-bound α-carbon to afford the active species. This complex undergoes intramolecular cyclization (C═C into Sc-imidazolyl insertion) with exo-selectivity, generating a ß-all-carbon-substituted quaternary center in the polycyclic imidazole derivative. The Sc-bound α-carbon deprotonates the imidazole C2-H bond to deliver the product and regenerate the active catalyst, which is the rate-determining step. Calculations illuminate the electronic effect of the ancillary Cp ligand on the catalyst activity and reveal the steric bias caused by using a chiral catalyst that induce the enantioselectivity. The insights can have implications for advancing rare-earth metal-catalyzed C-H functionalization of imidazoles.

Asymmetric Alkenyl C-H Functionalization by Cpx RhIII forms 2H-Pyrrol-2-ones through [4+1]-Annulation of Acryl Amides and Allenes.

An efficient Cpx RhIII -catalyzed enantioselective alkenyl C-H functionalization/[4+1] annulation of acryl amides and allenes is reported. The described transformation provides straightforward access to enantioenriched α,ß-unsaturated-γ-lactams bearing a quaternary stereocenter. The reaction operates under mild conditions, displays a broad functional-group tolerance, and provides 2H-pyrrol-2-ones with excellent selectivity of up to 97:3 er. Such scaffolds are frequently found in natural products and synthetic bioactive compounds and are of significant synthetic value. It is noteworthy that the allene serves as a one-carbon unit in the [4+1]-annulation.

An Enantioselective Cpx Rh(III)-Catalyzed C-H Functionalization/Ring-Opening Route to Chiral Cyclopentenylamines.

A chiral Cpx RhIII catalyst system in situ generated from a Cpx RhI (cod) precatalyst and bis(o-toluoyl) peroxide as activating oxidant was developed for a C-H activation/ring-opening sequence between aryl ketoxime ethers and 2,3-diazabicyclo[2.2.1]hept-5-enes. This transformation provides access to densely functionalized chiral cyclopentenylamines in excellent yields and enantioselectivities of up to 97:3 er. The reported method is also well suitable for asymmetric alkenyl C-H functionalizations of α,ß-unsaturated oxime ethers, furnishing skipped dienes with high levels of enantiocontrol.

Zafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental mice.

BACKGROUND: Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice. MATERIALS AND METHODS: The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleoti-dyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10 days postinjury. RESULTS: The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E2 (PGE2), and LTB4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function. CONCLUSION: The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL.

A Readily Accessible Class of Chiral Cp Ligands and their Application in RuII -Catalyzed Enantioselective Syntheses of Dihydrobenzoindoles.

Chiral cyclopentadienyl (Cpx ) ligands have a large application potential in enantioselective transition-metal catalysis. However, the development of concise and practical routes to such ligands remains in its infancy. We present a convenient and efficient two-step synthesis of a novel class of chiral Cpx ligands with tunable steric properties that can be readily used for complexation, giving Cpx RhI , Cpx IrI , and Cpx RuII complexes. The potential of this ligand class is demonstrated with the latter in the enantioselective cyclization of azabenzonorbornadienes with alkynes, affording dihydrobenzoindoles in up to 98:2 e.r., significantly outperforming existing binaphthyl-derived Cpx ligands.

Mimicking Synaptic Plasticity and Neural Network Using Memtranstors.

Artificial synaptic devices that mimic the functions of biological synapses have drawn enormous interest because of their potential in developing brain-inspired computing. Current studies are focusing on memristive devices in which the change of the conductance state is used to emulate synaptic behaviors. Here, a new type of artificial synaptic devices based on the memtranstor is demonstrated, which is a fundamental circuit memelement in addition to the memristor, memcapacitor, and meminductor. The state of transtance (presented by the magnetoelectric voltage) in memtranstors acting as the synaptic weight can be tuned continuously with a large number of nonvolatile levels by engineering the applied voltage pulses. Synaptic behaviors including the long-term potentiation, long-term depression, and spiking-time-dependent plasticity are implemented in memtranstors made of Ni/0.7Pb(Mg1/3 Nb2/3 )O3 -0.3PbTiO3 /Ni multiferroic heterostructures. Simulations reveal the capability of pattern learning in a memtranstor network. The work elucidates the promise of memtranstors as artificial synaptic devices with low energy consumption.

microRNA-19a protects osteoblasts from dexamethasone via targeting TSC1.

Activation of mTOR complex 1 (mTORC1) could protect human osteoblasts from dexamethasone. Tuberous sclerosis complex 1 (TSC1) is mTORC1 upstream inhibitory protein. We demonstrate here that microRNA-19a ("miR-19a", -3p) targets the 3' untranslated regions of TSC1 mRNA. Expression of miR-19a downregulated TSC1 in OB-6 osteoblastic cells and primary human osteoblasts. miR-19a activated mTORC1 and protected human osteoblasts from dexamethasone. mTORC1 inhibition, by RAD001 or Raptor shRNA, almost completely abolished miR-19a-induced osteoblast cytoprotection against dexamethasone. Knockdown of TSC1 by targeted shRNA similarly induced mTORC1 activation and protected osteoblasts. Moreover, miR-19a activated mTORC1-dependent NF-E2-related factor 2 (Nrf2) signaling and inhibited dexamethasone-induced reactive oxygen species production in osteoblasts. Together, miR-19a protects human osteoblasts from dexamethasone possibly via targeting TSC1-mTORC1 signaling.

Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence.

A highly efficient synthesis of enantioenriched spiroindolines by catalytic asymmetric dearomatization of indolyl dihydropyridines through a chiral phosphoric acid catalyzed enamine isomerization/spirocyclization/transfer hydrogenation sequence has been developed. This reaction proceeds under mild reaction conditions, affording novel spiroindolines in good yields (up to 88 %) with excellent enantioselectivity (up to 97 % ee). DFT calculations provide insights into the reaction mechanism as well as the origin of stereochemistry.

Activation of AMP-activated protein kinase by compound 991 protects osteoblasts from dexamethasone.

Dexamethasone (Dex) induces direct cytotoxicity to cultured osteoblasts. The benzimidazole derivative compound 991 ("C991") is a novel and highly-efficient AMP-activated protein kinase (AMPK) activator. Here, in both MC3T3-E1 osteoblastic cells and primary murine osteoblasts, treatment with C991 activated AMPK signaling, and significantly attenuated Dex-induced apoptotic and non-apoptotic cell death. AMPKα1 knockdown (by shRNA), complete knockout (by CRISPR/Cas9 method) or dominant negative mutation (T172A) not only blocked C991-mediated AMPK activation, but also abolished its pro-survival effect against Dex in osteoblasts. Further studies showed that C991 boosted nicotinamide adenine dinucleotide phosphate (NADPH) activity and induced mRNA expression of NF-E2-related factor 2 (Nrf2)-regulated genes (heme oxygenase-1 and NADPH quinone oxidoreductase 1). Additionally, C991 alleviated Dex-induced reactive oxygen species (ROS) production in osteoblasts. Notably, genetic AMPK inhibition reversed the anti-oxidant actions by C991 in Dex-treated osteoblasts. Together, we conclude that C991 activates AMPK signaling to protect osteoblasts from Dex.

Albumin-Conjugated Lipid-Based Multilayered Nanoemulsion Improves Drug Specificity and Anti-Inflammatory Potential at the Spinal Cord Injury gSite after Intravenous Administration.

Albumin-conjugated multilayered nanoemulsion (albumin-MNE) of methyl prednisolone (MP) was developed to ensure the specificity of the drug at the spinal cord injury (SCI) site. MNE was prepared by emulsification followed by ionic deposition of oppositely charged polymer followed by albumin conjugation using N-hydroxysuccinimide. Prepared nanoemulsion was characterized for particle size, polydispersity index (PDI), zeta potential (Zp), pH, viscosity, and entrapment efficiency. It was further evaluated for shape and morphological analysis, in vitro release, cell viability, and in vivo efficacy against post SCI-like conditions in terms of behavioral assessment, histopathological evaluation, and immunoflorescence assay of the histological sections showing Bax-driven apoptosis. Entrapment efficiency, particle size, PDI, and Zp of spherical-shaped, smooth-surfaced MNE droplets were found to be 68.9%, 83.2 ± 14.4 nm, 0.231, and + 62.7 mV, respectively. In vitro release of MP from MNE and albumin-MNE was observed to be 68.5 and 72.2% after 96th hour of the study. MNE showed higher viability of astrocytes than MP solution. Albumin-MNE improved behavior of SCI rat and histopathological conditions in a very effective manner when compared with MNE. Immunoflorescence assay reveals explicit decline in mitochondrial-mediated apoptosis by sub-cellular upregulation of Bax at spinal cord injury site. In conclusion, albumin-MNE delivered MP specifically at SCI site and avoided its instant availability inside astrocytes culture. On account of which the chitosan stabilized, lecithin-emulsified, multilayered nanoemulsion of MP depicts higher efficacy and safety than MNE and may offer safe and effective mean for the treatment of post SCI-like conditions in human.

MicroRNA-200a activates Nrf2 signaling to protect osteoblasts from dexamethasone.

Treatment with dexamethasone in human osteoblasts leads to oxidative stress and cell injures. NF-E2-related factor 2 (Nrf2) is a key anti-oxidant signaling. We want to induce Nrf2 activation via microRNA-mediated silencing its suppressor Keap1. Our results show that microRNA-200a ("miR-200a") expression depleted Keap1, causing Nrf2 protein stabilization in OB-6 osteoblastic cells. Reversely, the miR-200a anti-sense led to Keap1 upregulation and Nrf2 degradation. miR-200a expression activated Nrf2 signaling, which inhibited dexamethasone-induced reactive oxygen species production and OB-6 cell death/apoptosis. Keap1 shRNA also activated Nrf2 and protected OB-6 cells from dexamethasone. Importantly, miR-200a was in-effective in Keap1-silenced (by shRNA) OB-6 cells. In the primary human osteoblasts, Keap1 silence by targeted-shRNA or miR-200a protected cells from dexamethasone. Significantly, miR-200a level was decreased in necrotic femoral head tissues, which was correlated with Keap1 mRNA upregulation. Together, miR-200a expression activates Nrf2 signaling and protects human osteoblasts from dexamethasone.

Activation of Nrf2 by MIND4-17 protects osteoblasts from hydrogen peroxide-induced oxidative stress.

MIND4-17 is a recently developed NF-E2-related factor 2 (Nrf2) activator, which uniquely causes Nrf2 disassociation from Keap1. Here, we showed that pretreatment with MIND4-17 significantly inhibited hydrogen peroxide (H2O2)-induced viability reduction of primary osteoblasts and OB-6 osteoblastic cells. Meanwhile, MIND4-17 inhibited both apoptotic and non-apoptotic osteoblast cell death by H2O2. MIND4-17 treatment induced Keap1-Nrf2 disassociation, causing Nrf2 stabilization, accumulation and nuclear translocation in osteoblasts, leading to transcription of several Nrf2-dependent genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), γ-glutamylcysteine synthetase modifier subunit (GCLM) and catalytic subunit (GCLC). Additionally, MIND4-17 largely attenuated H2O2-reactive oxygen species (ROS) production, lipid peroxidation and DNA damages. Nrf2 knockdown by targeted short hairpin RNA (shRNA) exacerbated H2O2-induced cytotoxicity in OB-6 osteoblastic cells, and nullified MIND4-17-mediated cytoprotection against H2O2. Meanwhile, Keap1 shRNA took over MIND4-17's actions and protected OB-6 cells from H2O2. Together, MIND4-17 activates Nrf2 signaling and protects osteoblasts from H2O2.