A Metal-Free Direct Decarboxylative Fluoroacylation of Indole Carboxylic Acids with Fluorinated Acids.

A straightforward preparation of diversified fluorinated indol-3-yl ketones was developed by the direct decarboxylative fluoroacylation of indole carboxylic acids. The reaction could be performed on a gram scale under net conditions. Neither a metal catalyst nor an additive was employed. This methodology featured simple reaction conditions, high efficiency, exclusive selectivity, a broad substrate scope, and easy operation, which allowed it to meet the green chemistry requirement of the modern pharmaceutical industry. Control experiments confirmed that a radical process might be involved in the tandem decarboxylative fluoroacylation sequence.

Palladium-Catalyzed Intermolecular Dearomatization Annulation Cascade Reaction of Furans for Stereoselective Access to 2,5-Dihydrofurans.

A novel palladium-catalyzed intermolecular dearomatization of furans with alkynes via a three-component formal [3 + 2] spiroannulation/allylic substitution cascade reaction has been successfully developed for the stereoselective assembly of spiro 2,5-dihydrofuran frameworks. High step economy and efficacy as well as excellent stereoselectivity were achieved for a broad substrate scope. Two new C-C bonds and one new C-O bond were generated sequentially in a one-pot manipulation. The yielded spiro 2,5-dihydrofuran skeleton bearing a tetrasubstituted carbon center constitutes the core structure for plenty of useful natural products or corresponding analogues. This work represents a significant advancement in the dearomatization strategy for furan heterocycles and provides a practical methodology for expedited access to complex spiro dihydrofuran scaffolds.

Iridium-Catalyzed Direct Ortho-C-H Amidation of α-Ketoesters with Sulfonyl Azides Using a Transient Directing Group Strategy.

Direct C-H amidation of α-ketoesters was accomplished using various organic azides as the amino source through the combination of transient directing group strategy and iridium catalysis. Excellent functional group tolerance and wide substrate scope were explored under simple and mild conditions. Importantly, it was found that the steric hindrance of the ester moiety played a pivotal role for the reaction efficacy. In addition, the reaction could be enlarged to gram scale, and several useful heterocycles were readily constructed via one-step late-stage derivatization.

Direct Assembly of Diverse Unsymmetrical Tertiary 9-Fluorenols via Transient Directing Group-Enabled Palladium-Catalyzed Dual C-H Bond Activation of α-Ketoesters.

An expeditious construction of an unsymmetrical tertiary 9-fluorenol skeleton was accomplished starting from readily available α-ketoester and aryl iodide. Inexpensive commercially available substituted aniline was utilized as a potent monodentate transient directing group (TDG) to assist palladium-catalyzed direct ortho-C-H arylation and tandem dual C-H activation of α-ketoesters to form two carbon-carbon bonds. To demonstrate practical applications, the reaction was enlarged to the gram scale, and subsequent one-step derivatization allowed facile access to structurally diversified useful derivatives. A series of control experiments were carried out to shed light on the possible catalytic mechanism.

Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction.

Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to ɑ-ketoglutaric acid (α-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors. All these compounds were evaluated for their inhibition on mutant IDH1 enzyme activity. The structure-activity relationship was discussed on the basis of experimental data, with an attempt to pave the way for future studies. Among them, 43 exhibited potent and selective enzyme inhibitory activity, and showed strong binding affinity with mutant IDH1. It can decrease the cellular concentration of 2-HG, and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells by selectively inhibiting the activity of mutant IDH1.

A Metal-Free Visible-Light Photoredox Construction and Direct C-H Functionalization of Pyridines: Green Synthesis of Polysubstituted Picolinaldehydes.

The development of a novel environmental benign and sustainable synthetic method for highly efficient construction and direct C-H functionalization of N-heterocycles remains a pivotal central research topic for organic and medicinal chemistry. Herein, a novel visible-light-enabled biomimetic aza-6π electrocyclization for efficient assembly of diverse pyridines and further tandem Minisci-type reaction were developed. A broad spectrum of polysubstituted picolinaldehydes were readily constructed with high efficacy and good functional group tolerance under metal- and oxidant-free conditions.

Novel PROTACs for degradation of SHP2 protein.

Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, non-small cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.

Enantioselective Organocatalytic Four-Atom Ring Expansion of Cyclobutanones: Synthesis of Benzazocinones.

An enantioselective Michael addition- four-atom ring expansion cascade reaction involving cyclobutanones activated by a N-aryl secondary amide group and ortho-amino nitrostyrenes has been developed for the preparation of functionalized eight-membered benzolactams using bifunctional aminocatalysts. Taking advantage of the secondary amide activating group, the eight-membered cyclic products could be further rearranged into their six-membered isomers having a glutarimide core under base catalysis conditions without erosion of optical purity, featuring an overall ring expansion- ring contraction strategy.

Organocatalytic Asymmetric Reduction of Fluorinated Alkynyl Ketimines.

Highly chemoselective catalytic transfer hydrogenation of fluorinated alkynyl ketimines has been achieved by employing chiral phosphoric acid as a catalyst with benzothiazoline as a hydride source, providing the corresponding chiral fluorinated propargylamines in good yields and excellent enantioselectivities. In addition, iodocyclization of fluorinated propargylamine affords chiral 3-iodo-2-(trifluoromethyl)-1,2-dihydroquinoline, which can be easily converted to 2-(trifluoromethyl)- 1,2-dihydroquinoline derivatives with the selective COX-2 inhibitory activity.

Rhodium-Catalyzed Asymmetric N-H Functionalization of Quinazolinones with Allenes and Allylic Carbonates: The First Enantioselective Formal Total Synthesis of (-)-Chaetominine.

An unprecedented asymmetric N-H functionalization of quinazolinones with allenes and allylic carbonates was successfully achieved by rhodium catalysis with the assistance of chiral bidentate diphosphine ligands. The high efficiency and practicality of this method was demonstrated by a low catalyst loading of 1 mol % as well as excellent chemo-, regio-, and enantioselectivities with broad functional group compatibility. Furthermore, this newly developed strategy was applied as key step in the first enantioselective formal total synthesis of (-)-chaetominine.

An Expedient Total Synthesis of Triciribine.

In the present paper, we report an expedient total synthesis of triciribine, a tricyclic 7-deazapurine nucleoside and protein kinase B (AKT ) inhibitor, in 35% overall yield. Our synthesis route features a highly regioselective substitution of 1-N-Boc-2-methylhydrazine and a trifluoroacetic acid catalyzed one-pot transformation which combined the deprotection of the tert-butylcarbonyl (Boc) group and ring closure reaction together to give a tricyclic nucleobase motif.

First total synthesis of kipukasin A.

In this paper, a practical approach for the total synthesis of kipukasin A is presented with 22% overall yield by using tetra-O-acetyl-ß-D-ribose as starting material. An improved iodine-promoted acetonide-forming reaction was developed to access 1,2-O-isopropylidene-α-D-ribofuranose. For the first time, ortho-alkynylbenzoate was used as protecting group for the 5-hydoxy group. After subsequent Vorbrüggen glycosylation, the protecting group could be removed smoothly in the presence of 5 mol % Ph3PAuOTf in dichloromethane to provide kipukasin A in high yield and regioselectivity.

Merging asymmetric Henry reaction with organocatalytic cascade reaction for the construction of a chiral indolizidine alkaloid skeleton.

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral ß-nitro alcohol and α,ß-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Correction: The transformation from amorphous iron phosphate to sodium iron phosphate in sodium-ion batteries.

Correction for 'The transformation from amorphous iron phosphate to sodium iron phosphate in sodium-ion batteries' by Yao Liu et al., Phys. Chem. Chem. Phys., 2015, 17, 22144-22151.

The transformation from amorphous iron phosphate to sodium iron phosphate in sodium-ion batteries.

In this article, the structure and electrochemical performance of sodiated iron phosphate (FePO4) synthesized by the micro-emulsion technique have been investigated by X-ray diffraction (XRD), high resolution transmission electron microscopy (HRTEM) and electrochemical measurement. The results reveal that amorphous FePO4 could be transformed into crystallite sodium iron phosphate (NaFePO4) during electrochemical sodiation. Furthermore, the results of electrochemical testing show that the initial specific-discharge capacity of FePO4 is 142 mA h g(-1), and it still delivers a reversible capacity of 130.8 mA h g(-1) after 120 cycles. The discharge capacities could attain values of 142 mA h g(-1), 119.1 mA h g(-1), 91.5 mA h g(-1) and 63.5 mA h g(-1) at 0.1 C, 0.2 C, 0.5 C and 1 C, respectively. These findings have indicated that NaFePO4 has been formed during the electrochemical process and that amorphous structured FePO4 is one of the most promising "host" materials.

Cross-coupling/annulations of quinazolones with alkynes for access to fused polycyclic heteroarenes under mild conditions.

Ruthenium-catalyzed regioselective oxidative cross-coupling/annulations of quinazolones with alkynes were successfully developed for direct access to fused polycyclic heteroarenes. The transformation proceeded well with a broad substrate scope under mild conditions to achieve moderate to high yields.

Synthesis of 4-alkynylquinazolines: Pd-Cu-cocatalyzed coupling of quinazoline-4-tosylates with terminal alkynes using N-heterocyclic carbenes as ligands.

A Pd-Cu-cocatalyzed coupling reaction of quinazoline-4-tosylates with terminal alkynes using N-heterocyclic carbenes (NHC) as ligands is described, providing 4-alkynylquinazolines in good to excellent yields. This transformation proceeds under mild conditions with high efficiency, which is attractive for focused compound library construction.

DNA damage induced PARP-1 overactivation confers paclitaxel-induced neuropathic pain by regulating mitochondrial oxidative metabolism.

AIMS: Poly (ADP-ribose) polymerase (PARP) has been extensively investigated in human cancers. Recent studies verified that current available PARP inhibitors (Olaparib or Veliparib) provided clinical palliation of clinical patients suffering from paclitaxel-induced neuropathic pain (PINP). However, the underlying mechanism of PARP overactivation in the development of PINP remains to be investigated. METHODS AND RESULTS: We reported induction of DNA oxidative damage, PARP-1 overactivation, and subsequent nicotinamide adenine dinucleotide (NAD+) depletion as crucial events in the pathogenesis of PINP. Therefore, we developed an Olaparib PROTAC to achieve the efficient degradation of PARP. Continuous intrathecal injection of Olaparib PROTAC protected against PINP by inhibiting the activity of PARP-1 in rats. PARP-1, but not PARP-2, was shown to be a crucial enzyme in the development of PINP. Specific inhibition of PARP-1 enhanced mitochondrial redox metabolism partly by upregulating the expression and deacetylase activity of sirtuin-3 (SIRT3) in the dorsal root ganglions and spinal cord in the PINP rats. Moreover, an increase in the NAD+ level was found to be a crucial mechanism by which PARP-1 inhibition enhanced SIRT3 activity. CONCLUSION: The findings provide a novel insight into the mechanism of DNA oxidative damage in the development of PINP and implicate PARP-1 as a possible therapeutic target for clinical PINP treatment.

CloudBrain-MRS: An intelligent cloud computing platform for in vivo magnetic resonance spectroscopy preprocessing, quantification, and analysis.

Magnetic resonance spectroscopy (MRS) is an important clinical imaging method for diagnosis of diseases. MRS spectrum is used to observe the signal intensity of metabolites or further infer their concentrations. Although the magnetic resonance vendors commonly provide basic functions of spectrum plots and metabolite quantification, the spread of clinical research of MRS is still limited due to the lack of easy-to-use processing software or platform. To address this issue, we have developed CloudBrain-MRS, a cloud-based online platform that provides powerful hardware and advanced algorithms. The platform can be accessed simply through a web browser, without the need of any program installation on the user side. CloudBrain-MRS also integrates the classic LCModel and advanced artificial intelligence algorithms and supports batch preprocessing, quantification, and analysis of MRS data from different vendors. Additionally, the platform offers useful functions: (1) Automatically statistical analysis to find biomarkers for diseases; (2) Consistency verification between the classic and artificial intelligence quantification algorithms; (3) Colorful three-dimensional visualization for easy observation of individual metabolite spectrum. Last, data of both healthy subjects and patients with mild cognitive impairment are used to demonstrate the functions of the platform. To the best of our knowledge, this is the first cloud computing platform for in vivo MRS with artificial intelligence processing. We have shared our cloud platform at MRSHub, providing at least two years of free access and service. If you are interested, please visit https://mrshub.org/software_all/#CloudBrain-MRS or https://csrc.xmu.edu.cn/CloudBrain.html.

Magnetic Resonance Spectroscopy Quantification Aided by Deep Estimations of Imperfection Factors and Macromolecular Signal.

OBJECTIVE: Magnetic Resonance Spectroscopy (MRS) is an important technique for biomedical detection. However, it is challenging to accurately quantify metabolites with proton MRS due to serious overlaps of metabolite signals, imperfections because of non-ideal acquisition conditions, and interference with strong background signals mainly from macromolecules. The most popular method, LCModel, adopts complicated non-linear least square to quantify metabolites and addresses these problems by designing empirical priors such as basis-sets, imperfection factors. However, when the signal-to-noise ratio of MRS signal is low, the solution may have large deviation. METHODS: Linear Least Squares (LLS) is integrated with deep learning to reduce the complexity of solving this overall quantification. First, a neural network is designed to explicitly predict the imperfection factors and the overall signal from macromolecules. Then, metabolite quantification is solved analytically with the introduced LLS. In our Quantification Network (QNet), LLS takes part in the backpropagation of network training, which allows the feedback of the quantification error into metabolite spectrum estimation. This scheme greatly improves the generalization to metabolite concentrations unseen in training compared to the end-to-end deep learning method. RESULTS: Experiments show that compared with LCModel, the proposed QNet, has smaller quantification errors for simulated data, and presents more stable quantification for 20 healthy in vivo data at a wide range of signal-to-noise ratio. QNet also outperforms other end-to-end deep learning methods. CONCLUSION: This study provides an intelligent, reliable and robust MRS quantification. SIGNIFICANCE: QNet is the first LLS quantification aided by deep learning.