Chemoselective C-H Hydroxylation and Borylation of N-Phenylbenzamides using BBr3.

A novel metal-free chemoselective C-H hydroxylation and borylation of N-phenylbenzamides using BBr3 is described. The protocol generates the corresponding phenols and arylboronic esters in moderate to excellent yields under mild conditions with brilliant chemoselectivity. Additionally, this strategy can be realized in one pot, and several potential bioactive derivatives can be synthesized efficiently. Density functional theory calculations certify that the preferred pathway for this metal-free C-H hydroxylation process is the formation of a five-membered boracycle.

Recent advancements in the discovery of small-molecule non-nucleoside inhibitors targeting SARS-CoV-2 RdRp.

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 plays a pivotal role in the life cycle of the novel coronavirus and stands as a significant and promising target for anti-SARS-CoV-2 drugs. Non-nucleoside inhibitors (NNIs), as a category of compounds directed against SARS-CoV-2 RdRp, exhibit a unique and highly effective mechanism, effectively overcoming various factors contributing to drug resistance against nucleoside inhibitors (NIs). This review investigates various NNIs, including both natural and synthetic inhibitors, that closely interacting with the SARS-CoV-2 RdRp with valid evidences from in vitro and in silico studies.

C-H Borylation of Benzophenones Using Hydrazone as the Traceless Directing Group.

C-H borylation is one of the powerful C-H bond functionalization reactions. In this context, a metal-free C-H borylation of benzophenones using hydrazone as the traceless directing group has been reported. The dibromoboron intermediates can be obtained in excellent yields, and the corresponding arylboronic esters are generated in moderate to excellent yields. Furthermore, the borylated compounds can be transformed in a one-pot method, avoiding the loss of overall yield caused by the separation of the arylboronic esters.

Tandem C-C/C-N Bond Formation via Rh(III)-Catalyzed α-Fluoroalkenylation and Sequential Annulation of 2-Arylquinazolinones and gem-Difluorostyrenes.

An efficient method of Rh(III)-catalyzed coupling reaction between 2-arylquinazolinones and gem-difluorostyrenes has been developed. In this work, two diverse structures of monofluoroalkenes and isoindolo[1,2-b]quinazolin-10(12H)-one derivatives were respectively synthesized by controlling the amount of additives (Ca(OH)2 and AgNTf2) to achieve controlled stepwise breaking of the C-F bonds of gem-difluorostyrenes. This reaction has the characteristics of a wide range of substrates and good functional group tolerance. Meanwhile, several control experiments were conducted and a plausible mechanism was proposed.

Adamantane-1-Carbonyl-Directed C-H Borylation and Hydroxylation of Benzenethiols.

A novel route has been described for C-H borylation and hydroxylation of benzenethiols directed by adamantane-1-carbonyl using BBr3. The protocol generates corresponding arylboronic esters and phenols in moderate to excellent yields under metal-free conditions. In addition, the borylated product can be transformed and the directing group can be removed in good yields, which will facilitate the synthesis of structurally diverse benzenethiols.

Ligand-Enabled Sequential C(sp3)-H and C(sp2)-H Diolefination Reaction via Palladium Catalyst.

Palladium-catalyzed sequential C(sp3)-H and C(sp2)-H bond diolefination reaction of o-toluidine has been realized for the first time using acetyl-protected aminoethyl phenyl thioether ligands. This novel reaction allows for preparation of the conjugated diene structure via an immediate second olefination on the basis of the first C(sp3)-H olefination in one pot. Various triflyl-protected anilines and acrylates were used as coupling partners elegantly. Furthermore, the unpurified diolefination products can be easily converted to tetrahydroquinoline derivatives.

Metal-Free Boron-Mediated ortho-C-H Hydroxylation of N-Benzyl-3,4,5-tribromopyrazoles.

A novel route has been reported for C-H hydroxylation of benzyl compounds directed by a 3,4,5-tribromopyrazole auxiliary via boronation/oxidation using BBr3 and NaBO3·4H2O. The strategy exhibits outstanding site selectivity and affords the corresponding phenols in moderate to excellent yields under metal-free conditions. Besides, this protocol can be achieved in one pot, which is highly promising as a practical method for use in a multistep organic synthetic process.

Rhodium(III)-catalyzed cascade C-H functionalization/annulation of sulfoximines with iodonium ylides for the synthesis of cyclohexanone-1,2-benzothiazines.

A highly efficient Rh(III)-catalyzed cascade C-H activation/annulation of sulfoximines with iodonium ylides under metal-oxidant-free conditions has been reported. The fused cyclohexanone-1,2-benzothiazine scaffold is readily achieved with a one-pot process in this reaction. This protocol exhibits good functional group tolerance and moderate to excellent yields. Additionally, the olefination of the target product illustrates the promising usefulness of this strategy.

Ligand-Enabled C-H Olefination and Lactonization of Benzoic Acids and Phenylacetic Acids via Palladium Catalyst.

A novel ligand propan-2-one O-(p-tolylcarbamoyl) oxime (L7) has been developed to promote C(sp2)-H olefination of benzoic acids and phenylacetic acids via a palladium catalyst. With the subsequent lactonization of the olefinated products through 1,4-addition, highly monoselective cyclic lactone products of benzofuranones and benzopyrones were obtained in moderate to excellent yields. The DFT calculation demonstrated that the novel ligand propan-2-one O-(p-tolylcarbamoyl) oxime (L7) could improve the C-H activation reaction to give cyclic lactone products elegantly.

Palladium-Catalyzed ß-C(sp3)-H Arylation of Aliphatic Ketones Enabled by a Transient Directing Group.

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed ß-C(sp3)-H bond functionalization with 2-(aminooxy)-N,N-dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Metal-Free ortho-Selective C-H Borylation of 2-Phenylthiopyridines Using BBr3.

A novel route for ortho-selective C-H borylation of 2-phenylthiopyridines using BBr3 as the boron source under metal-free conditions has been reported. The reaction exhibited site exclusivity, and the synthesized aryl boronates were freely converted to various useful intermediates. Thus, this facile method would be beneficial to synthesize structurally diversified phenylthioethers derivatives and other materials containing boron-nitrogen coordination.

Rhodium(III)-catalyzed C4-amidation of indole-oximes with dioxazolones via C-H activation.

A novel method for the Rh(iii)-catalyzed oxime-directed C-H amidation of indoles with dioxazolones has been developed. This strategy provides an exclusive site selectivity and the directing group can be easily removed. This transformation features a wide substrate scope, good functional group tolerance and excellent yields, and may serve as a significant tool to construct structurally diverse indole derivatives for the screening of potential pharmaceuticals in the future.

Ruthenium(II)-Catalyzed α-Fluoroalkenylation of Oxime Ethers with gem-Difluorostyrenes via C-H Activation and C-F Cleavage.

A novel route for ruthenium(II)-catalyzed α-fluoroalkenylation of oxime ethers with gem-difluorostyrenes via C-H activation and C-F cleavage has been developed for the first time. Notably, the alkenyl units of products exhibit exclusive Z-configuration. This reaction features a broad substrate scope and good functional group tolerance. A plausible reaction mechanism is confirmed by an available cycloruthenated intermediate. Besides, the O-methyl oximyl-directing group can be readily removed to access the α-fluoroalkenylated acetophenones.

C-H Borylation of Diphenylamines through Adamantane-1-carbonyl Auxiliary by BBr3.

A method for ortho-C-H borylation of diphenylamines using BBr3 as the boron source has been reported. The noncatalytic adamantane-1-carbonyl directed reaction exhibited site exclusivity and good functional group tolerance. Generally, the borylation occurred at the more electron-rich aromatic ring and the borylated products could be converted to various useful intermediates. Besides, the derived arylation and removal of auxiliary of the product could be achieved in a one-pot fashion.

Synthesis and biological activity of glycyrrhetinic acid derivatives as antitumor agents.

Glycyrrhetinic acid (GA) had been the star anticancer lead compound and appealed to many scientists all over the world; however, its antitumor activity was not potent enough. To improve GA's cytoxicity and explore the effect of bonding mode on antitumor activity, 32 compounds including GA-OH series (GO, esters in C-3 position) and GA-NH2 series (GN, with amide linkages in C-3 position) had been designed and synthesized. All the compounds were screened for in vitro cytotoxicity against A549, HepG2, MCF-7, Hela and MDCK cell lines. As a result, all the de-protected (without Boc group) derivatives showed much stronger cytotoxic activity than GA, and surprisingly enough, all the GN series of the compounds were more potent than GO series against various tumor cells. Among them, the compound 26 (amide linkages in C-3 position) exhibited stronger antitumor activity against A549 cell line (IC50 = 2.109 ±â€¯0.11 µM) than the positive drug cisplatin (IC50 = 9.001 ±â€¯0.37 µM). Further studies indicated that compound 26 could induce A549 apoptosis via nuclei fragmentation. The detection of apoptosis and cell cycle analysis indicated that compound 26 could induce the early apoptosis and prevent A549 cells transition from S to G2 phase. Furthermore, the structure-activity relationships were briefly discussed. Among which, current study displayed amide linkages in C-3 position could effectively enhance GA cytotoxicity, providing a new modification strategy for further study.

Natural Berberine-Based Chinese Herb Medicine Assembled Nanostructures with Modified Antibacterial Application.

The abuse of traditional antibiotics has caused a series of health problems including antimicrobial resistance, which threatens human health. Therefore, searching for broad sources of antimicrobial agents and developing multidimensional strategies to combat bacterial infections are urgent. Here, we reported two natural self-assembling modes between berberine (BBR) and flavonoid glycosides: nanoparticles (NPs) and nanofibers (NFs), which were both mainly governed by electrostatic and hydrophobic interactions. These two nanostructures exhibited different antibacterial properties from BBR. NPs showed significantly enhanced bacteriostatic activity, whereas NFs displayed a much weaker effect than BBR. The distinguishing properties can be attributed to the different spatial configurations and self-assembly processes of NPs and NFs. Flavonoid glycosides and BBR first formed a one-dimensional complex unit and subsequently self-assembled into three-dimensional nanostructures. With the hydrophilic glucuronic acid toward the outside, NPs exhibited stronger affinity to bacteria, thereby inducing the collapse of the bacteria population and the decrease in biofilm. In addition, in vitro hemolysis tests, cytotoxicity tests, and in vivo zebrafish toxicity evaluation showed that the obtained self-assemblies had good biocompatibility. This supramolecular self-assembly strategy can be applied to construct other nanoscale antibacterial drugs and thus provides weapons for the development of self-delivering drugs in bacterial infection treatment.

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin⁻Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis.

Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He⁻pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 µM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 µM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 µM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure⁻activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

Design, Synthesis and Biological Evaluation of Ligustrazine-Flavonoid Derivatives as Potential Anti-Tumor Agents.

In the clinic some anti-tumor drugs have shown damage to normal blood vessels, which could lead to vascular diseases. Therefore, it is necessary to evaluate the effects of anti-tumor drugs on normal blood vessels at the beginning of the drug design process. In this study, ligustrazine (TMP) and flavonoids were selected as raw materials. Sixteen novel TMP-flavonoid derivatives were designed and synthesized. Interestingly, compounds 14 and 16 were obtained by hydrolysis of a dihydroflavone to a chalcone under alkaline conditions. The cytotoxicity of the TMP-flavonoid derivatives was evaluated on five human tumor cell lines and one classical type of normal endothelial cell lines (HUVEC-12) by an MTT assay. Part of the derivatives showed better anti-tumor activities than the corresponding raw materials. Among them, compound 14 exhibited the closest activity to the positive control against the Bel-7402 cell line (IC50 = 10.74 ± 1.12 µM; DDP IC50 = 6.73 ± 0.37 µM) and had no toxicity on HUVEC-12 (IC50 > 40 µM). Subsequently, fluorescence staining and flow cytometry analysis indicated that compound 14 could induce apoptosis of Bel-7402 cell lines. Moreover, the structure-activity relationships of these derivatives were briefly discussed.

Synthesis and biological evaluation of podophyllotoxin derivatives as selective antitumor agents.

To improve podophyllotoxin's cytotoxicity and selective effect, twenty-two podophyllotoxin derivatives had been designed and synthesized. The cytotoxicity of these compounds was evaluated on A549, MCF-7, HepG2 and L-02 cell lines. As a result, most of the compounds were more potent than the positive drugs Etoposide (VP-16) and Doxorubicin which were widely used in clinical for antitumor. There were no magnitude differences about these de-protected (without Boc group) podophyllotoxin amino acid derivatives' cytotoxicity between three tumor cell lines and normal hepatic L-02 cells. Interestingly, some protected (with Boc group) amino acid derivatives and some ligustrazine derivatives showed high selectivity, especially the compound 2 (sarcosine derivative with Boc group). It exhibited highly selectivity both on the cancer cells and the normal cells. The IC50 of compound 2 was 9.5 ±â€¯0.03 nM, 132.6 ±â€¯24.1 nM, 96.4 ±â€¯1.3 nM and 160.2 ±â€¯4.7 nM against A549, MCF-7, HepG2 and L-02 cells, respectively. The SI (IC50L-02/IC50A549) value of compound 2, Doxorubicin and Etoposide was 16.9, 0.2 and 0.5, respectively. Meanwhile, SI (IC50MCF-7/IC50A549) value and SI (IC50HepG2/IC50A549) value of compound 2 were 14.0 and 10.1, respectively. In summary, compound 2 showed high selectivity especially on A549 cells. Further research on cell apoptosis indicated that compound 2 could induce apoptosis of A549 cells through nuclei fragmentation and had lower toxicity to normal hepatic L-02 cells. The detection of apoptosis and cell cycle analysis indicated that compound 2 induced A549 cells apoptosis and prevented A549 cells transition from S to G2 phase while there were no obvious changes on L-02 cells. Moreover, the structure-activity relationships of these derivatives were briefly discussed.

Novel Neuroprotective Lead Compound Ligustrazine Derivative Mass Spectrometry Fragmentation Rule and Metabolites in Rats by LC/LTQ-Orbitrap MS.

The neuroprotective evaluation of ligustrazine derivatives has become a research focus all over the world. A novel ligustrazine derivative, (3,5,6-Trimethylpyrazin-2-yl)methyl(E)-3-(4-((3,5,6-trimethylpyrazin-2-l)methoxy)phenyl)acrylate (T-CA), has shown protective effects against CoCl2-induced neurotoxicity in a differentiated PC12 cell model and middle cerebral artery occlusion (MCAO) model in our previous studies. However, nearly none of the parent drugs existed after rapid metabolism due to uncertain reasons. Thus, the fragmentation regularities of mass spectra, and metabolites, of T-CA in rats were examined using liquid chromatography-electrospray ionizationion trap mass spectrometry (LC/LTQ-Orbitrap MS) in this research. The main fragment ion, mass spectrum characteristics, and the structural information were elucidated. When compared with a blank sample, we identified five kinds of T-CA metabolites, including three phase I metabolites and two phase II metabolites. The results showed that the metabolic pathways of T-CA in rats via oral administration were hydrolysis (ether bond rupture, ester bond rupture), oxidation, reduction, glucose aldehyde acidification, etc. In addition, three main metabolites were synthesized and their structures were identified by superconducting high-resolution NMR and high-resolution mass spectroscopy (HR-MS). The neuroprotective activity of these metabolites was validated in a PC12 cell model. One of the metabolites (M2) showed significant activity (EC50 = 9.67 µM), which was comparable to the prototype drug T-CA (EC50 = 7.97 µM). The current study provides important information for ligustrazine derivatives, pertaining to the biological conversion process in vivo.