Tricyclic Aza-Andrographolide Derivatives from Late-Stage Hydroamination and Their Anti-human Coronavirus (Anti-HCoV) Activity.

A late-stage functionalization (LSF) of the natural product andrographolide for the efficient assembly of a range of structurally interesting and diverse tricyclic-aza derivatives was developed. The key to the diversification is a photo-catalyzed intramolecular hydroamination reaction, and acridinium derivatives were demonstrated to be the optimal catalysts. Additionally, the synthesized tricyclic aza-andrographolide derivatives were found to inhibit human coronavirus with high potency.

Combining visible-light induction and copper catalysis for chemo-selective nitrene transfer for late-stage amination of natural products.

Nitrene transfer chemistry is an effective strategy for introducing C-N bonds, which are ubiquitous in pharmaceuticals, agrochemicals and diverse bioactive natural products. The development of chemical methodology that can functionalize unique sites within natural products through nitrene transfer remains a challenge in the field. Herein, we developed copper catalyzed chemoselective allylic C-H amination and catalyst-free visible-light induced aziridination of alkenes through nitrene transfer. In general, both reactions tolerate a wide range of functional groups and occur with predictable regioselectivity. Furthermore, combination of these two methods enable the intermolecular chemo-selective late-stage amination of biologically active natural products, leading to C-H amination or C=C aziridination products in a tunable way. A series of control experiments indicate two-step radical processes were involved in both reaction systems.

Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination.

As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia-of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel 18F-aryl PDE10A PET radioligand, codenamed [18F]P10A-1910 ([18F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [18F]9 possessed good in vitro binding affinity (IC50 = 2.1 nmol/L) and selectivity towards PDE10A. Further, [18F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (P app > 10 × 10-6 cm/s in MDCK-MDR1 cells). PET imaging studies of [18F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [18F]9 when compared to the current reference standard for PDE10A-targeted PET, [18F]MNI659. Further, dose-response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [18F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [18F]9 is a promising PDE10A PET radioligand for clinical translation.

Comparison of flavonoids and phenylpropanoids compounds in Chinese water chestnut processed with different methods.

Different processing methods of Chinese water chestnut (CWC; Eleocharis dulcis (Burm.f.) Trin. ex Hensch.) steaming with skin (WPC), cooking with skin (WPS), steaming with peeling (PS), fresh cutting (FF) and cooking with peeling (PC) were compared. Liquid chromatography-mass spectrometry was used to analyze the metabolic profiles of the processed samples. A total of 454 metabolites, including 123 flavonoids and 57 phenylpropanoids, were characterized. The flavonoid and phenylpropanoid profiles were distinguished using PCA. Eighteen flavonoids and six phenylpropanoids were detected and quantitated in the WPC and WPS samples but not in the FF, PC and PS samples. In addition to the O-hexoside of tricin, kaempferol and luteolin were the predominant flavonoids in the WPC and WPS samples, and all three compounds were higher in the WPC and WPS samples than in the FF sample. This study provides new results regarding differences in the metabolite profile of CWC processed with different methods.

A planar and uncharged copper(II)-picolinic acid chelate: Its intercalation to duplex DNA by experimental and theoretical studies and electrochemical sensing application.

Using an external redox-active molecule as a DNA hybridization indicator is still a popular strategy in electrochemical DNA biosensors because it is label-free and the multi-site binding can enhance the response signal. A planar and uncharged transition metal complex, Cu(PA)2 (PA = picolinic acid) with excellent electrochemical activity has been synthesized and its interaction with double-stranded DNA (dsDNA) is studied by experimental electrochemical methods and theoretical molecular docking technology. The experimental results reveal that the copper complex interacts with dsDNA via specific intercalation, which is verified by the molecular docking result. The surface-based voltammetric analysis demonstrates that the planar Cu(PA)2 can effectively accumulate within the electrode-confined hybridized duplex DNA rather than the single-stranded probe DNA. Based on this phenomenon, the Cu(PA)2 is utilized as an electrochemical hybridization indicator for the detection of oligonucleotides. The sensing assays show that upon incubation in Cu(PA)2 solution, the probe electrode does not display any Faraday signal, but the hybridized one has a pair of strong redox peaks corresponding to the electrochemistry of Cu(PA)2, showing excellent hybridization indicating function of Cu(PA)2 without background interference. The signal intensity of Cu(PA)2 is dependent on the concentrations of the target oligonucleotide ranging from 1 fM to 100 nM with an experimental detection limit of 1.0 fM. Due to the specific intercalation of Cu(PA)2 with dsDNA, the biosensor also exhibits good ability to recognize oligonucleotide with different base mismatching degree.

Discovery of anti-inflammatory terpenoids from Mallotus conspurcatus croizat.

ETHNOPHARMACOLOGICAL RELEVANCE: Mallotus conspurcatus croizat (Euphorbiaceae), a plant native to Jinxiu in Guangxi, is popularly used in folk medicine to treat pelvic inflammatory disease. The anti-inflammatory activities of the compounds obtained from M. conspurcatus root were evaluated in this study. AIM OF THE STUDY: This study explored the major anti-inflammatory components of this plant. MATERIALS AND METHODS: The ethyl acetate fraction of the ethanol extract from M. conspurcatus was separated using chromatographic techniques. The structures of the isolates were elucidated from NMR, MS and X-ray data as well as from ECD. The anti-inflammatory activities of the isolates from M. conspurcatus were evaluated using LPS-stimulated RAW 264.7 cell models. The production of NO, TNF-α and PGE-2 was determined by ELISA and Griess tests. The expression levels of COX-2, NF-κB/p65 and iNOS were measured by western blotting. RESULTS: Two new diterpenoids, malloconspur A (1) and malloconspur B (2), and sixteen known terpenoids (3-18) were identified by comprehensive spectroscopic analyses and comparison with literature data. Malloconspur B (2) and 17-hydroxycleistantha-12,15-dien-3-one (3) substantially inhibited the release of NO with IC50 values of 10.47 µM and 9.32 µM, respectively. Compounds 1, 2 and 3 markedly decreased the secretion of PGE2 and TNF-α (P < 0.01) by LPS-induced RAW264.7 cells. Compounds 2 and 3 markedly decreased iNOS, NF-κB/p65 and COX-2 protein expression. CONCLUSIONS: Our identification of these diterpenoids provides strong evidence for the use of M. conspurcatus among the Yao people as a medicinal plant for the treatment of inflammation. The dramatic differences in the chemical structures of the active diterpenoids of this plant from those on the market suggest these compounds have potential as anti-inflammatory lead compounds for follow-up research.

Anti-inflammatory lignans and phenylethanoid glycosides from the root of Isodon ternifolius (D.Don) Kudô.

Five undescribed lignans, three undescribed phenylethanoid glycosides and eight known compounds were isolated from the root of Isodon ternifolius (D.Don) Kudô (Lamiaceae). The structures of all of the isolated constituents were characterized by physical data analyses including NMR, MS and ECD. The anti-inflammatory activities of the isolates were evaluated based on their ability to inhibit NO, PGE2 and TNF-α production in LPS-induced RAW 264.7 macrophage cells. Six phenyl-naphthalene lignans, ternifoliuslignan A, ternifoliuslignan B, ternifoliuslignan C, ternifoliuslignan D, ternifoliuslignan E and 3-carboxy-6,7-dihydroxy-1-(3',4'-dihydroxyphenyl) -naphthalene, can substantially inhibit the release of NO with IC50 values in the range of 9.98-29.14 µM, which are better than the positive reference. These phenyl-naphthalene lignans could markedly decrease the secretions of PGE2 and TNF-α in LPS-induced RAW264.7 cells. Ternifoliuslignan C and ternifoliuslignan D decreased iNOS, COX-2 and NF-κB/p65 protein expression. A preliminary structure-activity relationship among the phenyl-naphthalene lignans for the anti-inflammatory activity was discussed.

Two new coumarins from the bark of Streblus indicus (Bur.) Corner.

Two new coumarins 7-O-(6-O-(5-O-3,4,5-tri-methoxycinnamate-ß-d-apiofuranosyl-ß-d-glucopyranosyl)-6-methoxy coumarin (1) and 7-O-(6-O-(4-(2-hydroxy-1-hydroxymethyl-ethoxy)-3-methoxy-cinnamyl)-ß-d-glucopyranosyl)-6-methoxy coumarin (2), along with 10 known metabolites, were isolated from the bark of Streblus indicus, their structures were identified by comparison of experimental and published spectroscopic data. (S)-marmesinin (6) and scoparone (7) exhibited moderate antimicrobial activity in vitro against Staphylococcus aureus strain with the MIC values of 62.5 and 125.0 µg/mL, respectively. Betulinic acid showed inhibitory activity in vitro against MCF-7 cell with IC50 value of 9.5 ± 0.1 µM.