Detection and Identification of Nitrile Compounds via Recognition-Enabled Chromatographic 19F NMR.

The surge in applications of nitrile compounds across diverse fields, such as pharmaceuticals, agrochemicals, dyes, and functional materials, necessitates the development of rapid and efficient detection and identification methods. In this study, we introduce a chemosensing strategy employing a novel 19F-labeled probe, facilitating swift and accurate analysis of a broad spectrum of nitrile-containing analytes. This approach leverages the reversible interaction between the 19F-labeled probe and the analytes to produce chromatogram-like outputs, ensuring the precise identification of various pharmaceuticals and pesticides within complex matrices. Additionally, this dynamic system offers a versatile platform to investigate through-space 19F-19F interactions, showcasing its potential for future applications in mechanistic studies.

NMR-Based Chiral Discrimination of Bulky Amines with a 19F-Tagged NNO Pincer Complex.

Within pharmaceutical research, ensuring the enantiomeric purity of chiral compounds is critical. Specifically, chiral amines are a crucial category of compounds, due to their extensive therapeutic uses. However, the enantiomeric analysis of these compounds, particularly those with significant steric hindrance, remains a challenge. To address this issue, our research introduces a novel chiral 19F-tagged NNO palladium pincer probe, strategically engineered with an open binding site to accommodate bulky amines. This probe facilitates the enantiodifferentiation of such amines, as evidenced by the distinct 19F NMR signals generated by the enantiomers. Moreover, our findings highlight the probe's applicability in the chiral discrimination of various psychoactive substances, underscoring its potential for the identification of illegal stimulant use and contributing to forensic investigations.

Electron Donor-Acceptor Complex Driven Photocatalyst-Free Trifluoromethylation of Heterocycles.

Heterocyclic trifluoromethylation is efficiently initiated through a photochemical reaction utilizing an electron donor-acceptor (EDA) complex, proceeding smoothly without the use of photocatalysts, transition-metal catalysts, or additional oxidants. This method has been optimized through extensive experimentation, demonstrating its versatility and efficacy across various substrates, including quinoxalinones, coumarins, and indolones. Notably, this approach enables the practical synthesis of trifluoromethylated quinoxalinones on a gram scale. Mechanistic investigations that incorporate radical trapping and ultraviolet/visible spectroscopy, confirmed the formation of the an EDA complex and elucidated the reaction pathways. This study highlights the crucial role of EDA photoactivation in trifluoromethylation, significantly expanding the application scope of EDA complexes in chemical synthesis.

An unexpected role of EasDaf: catalyzing the conversion of chanoclavine aldehyde to chanoclavine acid.

Ergot alkaloids (EAs) are a diverse group of indole alkaloids known for their complex structures, significant pharmacological effects, and toxicity to plants. The biosynthesis of these compounds begins with chanoclavine-I aldehyde (CC aldehyde, 2), an important intermediate produced by the enzyme EasDaf or its counterpart FgaDH from chanoclavine-I (CC, 1). However, how CC aldehyde 2 is converted to chanoclavine-I acid (CC acid, 3), first isolated from Ipomoea violacea several decades ago, is still unclear. In this study, we provide in vitro biochemical evidence showing that EasDaf not only converts CC 1 to CC aldehyde 2 but also directly transforms CC 1 into CC acid 3 through two sequential oxidations. Molecular docking and site-directed mutagenesis experiments confirmed the crucial role of two amino acids, Y166 and S153, within the active site, which suggests that Y166 acts as a general base for hydride transfer, while S153 facilitates proton transfer, thereby increasing the acidity of the reaction. KEY POINTS: • EAs possess complicated skeletons and are widely used in several clinical diseases • EasDaf belongs to the short-chain dehydrogenases/reductases (SDRs) and converted CC or CC aldehyde to CC acid • The catalytic mechanism of EasDaf for dehydrogenation was analyzed by molecular docking and site mutations.

Anti-inflammatory Steroids from the South China Sea Sponge Spongia officinalis.

One new highly degraded steroid, namely 21-nor-4-ene-chaxine A (1) furnishing a 5/6/5-tricyclic, along with one known related analogue (2), were isolated from the South China Sea sponge Spongia officinalis. Their structures including absolute configurations were established by extensive spectroscopic data analysis, TDDFT-ECD calculation, and comparison with the spectral data previously reported in the literature. Compound 1 represent the new member of incisterols family with a highly degradation in ring B. In vitro bioassays revealed compound 2 exhibited significant anti-microglial inflammatory effect on lipopolysaccharide (LPS)-induced inflammation in BV-2 microglial cells.

Two Undescribed Coumarins from Notopterygium incisum with Anti-inflammatory Activity.

Two previously undescribed coumarins (1-2) were isolated from the root of Notopterygium incisum. The structures of new findings were elucidated by analyses of spectral evidences in HRESIMS, NMR, as well as ICD. The absolute configurations were further confirmed by chemical calculations. 1-2 exhibits obviously anti-inflammatory activity by inhibiting the expression of inflammatory mediators (COX-2, iNOS), as well as reducing the release of NO and the accumulation of ROS in cells. Western blotting analysis revealed that 2 could inhibit the PI3K/AKT pathway by reducing the expression of p-PI3K and p-AKT.

Enantioselective Reductive Cross-Couplings of Olefins by Merging Electrochemistry with Nickel Catalysis.

The merger of electrochemistry and transition metal catalysis has emerged as a powerful tool to join two electrophiles in an enantioselective manner. However, the development of enantioselective electroreductive cross-couplings of olefins remains a challenge. Inspired by the advantages of the synergistic use of electrochemistry with nickel catalysis, we present here a Ni-catalyzed enantioselective electroreductive cross-coupling of acrylates with aryl halides and alkyl bromides, which affords chiral α-aryl carbonyls in good to excellent enantioselectivity. Additionally, this catalytic reaction can be applied to (hetero)aryl chlorides, which is difficult to achieve by other methods. The combination of cyclic voltammetry analysis with electrode potential studies suggests that the NiI species activates aryl halides by oxidative addition and alkyl bromides by single-electron transfer.

Nanolobatone A, An Unprecedented Diterpenoid and Related New Casbanoids from the Hainan Soft Coral Sinularia nanolobata.

Nanolobatone A, featuring an unprecedented tricyclo[10.3.0.01,2 ]pentadecane carbon skeleton, along with four new polyoxygenated and four unusual endoperoxide-bridged casbane-type diterpenoids were isolated from the Hainan soft coral Sinularia nanolobata. The structures of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction analysis, and time-dependent density functional theory/electronic circular dichroism calculations. A plausible biosynthetic pathway of new isolates was proposed. Bioassays revealed that nanolobatone A showed weak antibacterial activity against the Gram-positive bacteria Streptococcus pyogenes.

Recent Advances in the Synthesis and Transformation of Carbamoyl Fluorides, Fluoroformates, and Their Analogues.

Carbamoyl fluorides, fluoroformates, and their analogues are a class of important compounds and have been evidenced as versatile building blocks for the preparation of useful molecules in organic chemistry. While major achievements were made in the synthesis of carbamoyl fluorides, fluoroformates, and their analogues in the last half of 20th century, an increasing number of reports have focused on using O/S/Se=CF2 species or their equivalents as the fluorocarbonylation reagents for the direct construction of these compounds from the parent heteroatom-nucleophiles in recent years. This review mainly summarizes the advances in the synthesis and typical application of carbamoyl fluorides, fluoroformates, and their analogues by the halide exchanges and fluorocarbonylation reactions since 1980.

Recent Advances in Carbon-Nitrogen/Carbon-Oxygen Bond Formation Under Transition-Metal-Free Conditions.

Carbon-heteroatom bond formation under transition-metal free conditions provides a powerful synthetic alternative for the efficient synthesis of valuable molecules. In particular, C-N and C-O bonds are two important types of carbon-heteroatom bonds. Thus, continuous efforts have been deployed to develop novel C-N/C-O bond formation methodologies involving various catalysts or promoters under TM-free conditions, which enables the synthesis of various functional molecules comprising C-N/C-O bonds in a facile and sustainable manner. Considering the significance of C-N/C-O bond construction in organic synthesis and materials science, this review aims to comprehensively present selected examples on the construction of C-N (including amination and amidation) and C-O (including etherification and hydroxylation) bonds without transition metals. Besides, the involved promoters/catalysts, substrate scope, potential application and possible reaction mechanisms are also systematically discussed.

Photoinduced Copper-Promoted Decarboxylative Trifluoromethylselenolation of Aromatic Carboxylic Acids with [Me4N][SeCF3].

Visible-light-induced decarboxylative trifluoromethylselenolation of (hetero)aromatic carboxylic acids with [Me4N][SeCF3], oxidant, and catalysts afforded a variety of (hetero)aryl trifluoromethyl selenoethers in good yields. The reaction might involve a radical process, which generated (hetero)aryl radicals from the stable (hetero)aromatic carboxylic acids via oxidative decarboxylation with NFSI as the oxidant, [di-tBu-Mes-Acr-Ph][BF4] as the photocatalyst, and 1,1'-biphenyl as the cocatalyst. Both catalysts had a decisive influence on the reaction. The trifluoromethylselenolation was further promoted by the copper salts probably via Cu-mediated cross-coupling of the sensitive SeCF3 species with the in situ formed (hetero)aryl radicals. Advantages of the method include visible light irradiation, mild reaction conditions at ambient temperature, good functional group tolerance, no pre-functionalization/activation of the starting carboxylic acids, and applicability to drug molecules. This protocol is promising and synthetically useful, which overcame the limitations of the known trifluoromethylselenolation methods and represented the first decarboxylative trifluoromethylselenolation of (hetero)aromatic carboxylic acids.

O-Alkylazoxymycins A-F, Naturally Occurring Azoxy-Aromatic Compounds from Streptomyces sp. Py50.

Six new azoxy-aromatic compounds (o-alkylazoxymycins A-F, 1-6) and two new nitrogen-bearing phenylvaleric/phenylheptanoic acid derivatives (o-alkylphemycins A and B, 7 and 8) were isolated from Streptomyces sp. Py50. Their structures were elucidated based on HRESIMS, NMR, UV spectroscopic analyses, and X-ray crystallographic data. O-Alkylazoxymycins A-F (1-6) are the first natural examples of azoxy compounds with the azoxy bond attached to the ortho-position of the phenylheptanoic acid or phenylvaleric acid moiety. Compounds 1, 5, and 6 were active against Epidermophyton floccosum with MIC50 values ranging from 10.1 to 51.2 µM. A plausible biosynthetic pathway of 2 and 3 was proposed.

2-Aminopyrimidine derivatives as selective dual inhibitors of JAK2 and FLT3 for the treatment of acute myeloid leukemia.

Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 µM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.

Comparative study of characteristic compounds of three species of truffle.

The Panxi area in Sichuan Province is the main area for the production of truffles in China, and several species of truffle are known to exist in this region. Nevertheless, it is unclear what the differences in chemical composition between the truffles are. Using an ultra-high-performance liquid chromatography quadrupole/orbitrap high-resolution mass spectrometry coupled with Compound Discoverer 3.0, we identified chemical components in three mainly known truffles from the Panxi region. Further analysis of chemical composition differences was conducted using principal component analysis, and orthogonal partial least squares discriminant analysis. Note that, 78.9% of the variance was uncovered by the principal component analysis model. As a result of the orthogonal partial least squares discriminant analysis model, the three species of truffles (Tuber pesudohimalayense, Tuber indicum, and Tuber sinense) from Panxi were better discriminated, with R2 X, R2 Y, and Q2 being 0.821, 0.993, and 0.947, respectively. In this study, 87 components were identified. T. pesudohimalayense contained significantly higher levels of nine different compounds than the other two species. Hence, it was possible to identify similarities and differences between three species of truffles from Panxi in terms of chemical composition. This can be used as a basis for quality control.

New Antibacterial Diterpenoids from the South China Sea Soft Coral Klyxum molle.

Fifteen new diterpenoids, namely xishaklyanes A-O (1-15), along with three known related ones (16-18), were isolated from the soft coral Klyxum molle collected from Xisha Islands, South China Sea. The stereochemistry of the new compounds was elucidated by a combination of detailed spectroscopic analyses, chemical derivatization, quantum chemical calculations, and comparison with the reported data. The absolute configuration of compound 18 was established by the modified Mosher's method for the first time. In bioassay, some of these compounds exhibited considerable antibacterial activities on fish pathogenic bacteria, and compound 4 showed the most effective activity with MIC of 0.225 µg/mL against Lactococcus garvieae.

Design, Synthesis, Antifungal Activity, and Molecular Docking of Streptochlorin Derivatives Containing the Nitrile Group.

Based on the structures of natural products streptochlorin and pimprinine derived from marine or soil microorganisms, a series of streptochlorin derivatives containing the nitrile group were designed and synthesized through acylation and oxidative annulation. Evaluation for antifungal activity showed that compound 3a could be regarded as the most promising candidate-it demonstrated over 85% growth inhibition against Botrytis cinerea, Gibberella zeae, and Colletotrichum lagenarium, as well as a broad antifungal spectrum in primary screening at the concentration of 50 µg/mL. The SAR study revealed that non-substituent or alkyl substituent at the 2-position of oxazole ring were favorable for antifungal activity, while aryl and monosubstituted aryl were detrimental to activity. Molecular docking models indicated that 3a formed hydrogen bonds and hydrophobic interactions with Leucyl-tRNA Synthetase, offering a perspective for the possible mechanism of action for antifungal activity of the target compounds.

Two New Cembranoids from the Chinese Soft Coral Sarcophyton boettgeri.

Two new cembranoids, namely sarcoboettgerols D and E, together with four known related ones, have been isolated from the soft coral Sarcophyton boettgeri collected from Weizhou Island in the South China Sea. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, quantum mechanical nuclear magnetic resonance methods, time-dependent density functional theory-electronic circular dichroism calculations, as well as comparison with the reported data in the literature. A plausible biogenetic relationship of four cembranoids was proposed. In bioassays, sarcomililatin B exhibited cytotoxic activity against H1299 cell (IC50 =35.0 µM), whereas sarcomililatin B and sarcomililatin A displayed moderate antibacterial activities (MIC 17.4-34.8 µg/mL).

Rapid recognition and targeted isolation of potential anti-breast cancer xanthones in Hypericum bellum Li by "seed" mass spectra-based molecular networking and in silico MS/MS fragmentation.

INSTRUCTION: Hypericum bellum Li is rich in xanthones with various bioactivities, especially in anti-breast cancer. While the scarcity of mass spectral data of xanthones in Global Natural Products Social Molecular Networking (GNPS) libraries have challenged the rapid recognition of xanthones with similar structures. OBJECTIVE: This study is aimed to enhance the molecular networking (MN)-based dereplication and visualisation ability of potential anti-breast cancer xanthones from H. bellum to overcome the scarcity of xanthones mass spectral data in GNPS libraries. Separating and purifying the MN-screening bioactive xanthones to verify the practicality and accuracy of this rapid recognition strategy. METHODOLOGY: A combined strategy of "seed" mass spectra-based MN, in silico annotation tools, substructure identification tools, reverse molecular docking, ADMET screening, molecular dynamics (MDs) simulation experiments, and an MN-oriented separation procedure was first introduced to facilitate the rapid recognition and targeted isolation of potential anti-breast cancer xanthones in H. bellum. RESULTS: A total of 41 xanthones could only be tentatively identified. Among them, eight xanthones were screened to have potential anti-breast cancer activities, and six xanthones that were initially reported in H. bellum were obtained and verified to have good binding abilities with their paired targets. CONCLUSION: This is a successful case study that validated the application of "seed" mass spectral data could overcome the drawbacks of GNPS libraries with limited mass spectra and enhance the accuracy and visualisation of natural products (NPs) dereplication, and this rapid recognition and targeted isolation strategy can be also applicable for other types of NPs.

Discovery and Engineering of the Cocaine Biosynthetic Pathway.

Cocaine, the archetypal tropane alkaloid from the plant genus Erythroxylum, has recently been used clinically as a topical anesthesia of the mucous membranes. Despite this, the key biosynthetic step of the requisite tropane skeleton (methylecgonone) from the identified intermediate 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid (MPOA) has remained, until this point, unknown. Herein, we identify two missing enzymes (EnCYP81AN15 and EnMT4) necessary for the biosynthesis of the tropane skeleton in cocaine by transient expression of the candidate genes in Nicotiana benthamiana. Cytochrome P450 EnCYP81AN15 was observed to selectively mediate the oxidative cyclization of S-MPOA to yield the unstable intermediate ecgonone, which was then methylated to form optically active methylecgonone by methyltransferase EnMT4 in Erythroxylum novogranatense. The establishment of this pathway corrects the long-standing (but incorrect) biosynthetic hypothesis of MPOA methylation first and oxidative cyclization second. Notably, the de novo reconstruction of cocaine was realized in N. benthamiana with the two newly identified genes, as well as four already known ones. This study not only reports a near-complete biosynthetic pathway of cocaine and provides new insights into the metabolic networks of tropane alkaloids (cocaine and hyoscyamine) in plants but also enables the heterologous synthesis of tropane alkaloids in other (micro)organisms, entailing significant implications for pharmaceutical production.

Trends of antimalarial marine natural products: progresses, challenges and opportunities.

Covering 1972 to 2021Malaria remains a significant public health problem in some regions of the world. The great efforts to control malaria have been severely compromised due to the widespread resistance of Plasmodium falciparum to nearly all frontline drugs. Pursuit of novel molecules from the sea will potentially result in new interventions against malaria, which are urgently needed to combat the increase of resistance. Focusing on the strategy of the "Blue Drug Bank", the molecules highlighted here can serve as an inspiration for future medicinal chemistry campaigns. This review covers the developments in the field of antimalarial marine lead compounds reported between 1972 and July 2021, and offers a comprehensive overview on their progresses and potentials. We selected 60 representative potential candidate molecules from 361 marine natural products, and highlighted their structure-activity relationships, molecular mechanisms of targets, and drug-like properties in order to assess their full potential to be developed. We summarized 107 clinically proven or potential antimalarial targets and their subcellular locations in the relevant target proteins, which linked the molecules to the target proteins at the subcellular level. Hence, it could be expected that natural products targeting different mechanisms may prove to be an effective strategy in antimalarial drug research and development in the future.