Synthesis of Sulfilimines via Selective S-C Bond Formation in Water.

Sulfilimines are valuable compounds both in organic synthesis and in pharmaceuticals. Here we developed a mild and simplified method for preparation of sulfilimines via selective S-C bond formation rather than traditional S-N bond formation. The method is both attractive and useful for the following reasons: it uses a readily available alkylation reagent such alkyl bromide or alkyl iodide, it uses water as solvent, it is easy to perform, and it is convenient for late-stage diversification of drugs.

Enantioselective Double Carbonylation Enabled by High-Valent Palladium Catalysis.

Palladium-catalyzed carbonylation reactions are efficient methods for synthesizing valuable molecules. However, realizing a carbonylation with excellent yield and chemo-, regio-, and enantioselectivities by classical low-valent palladium catalysis is highly challenging. Herein, we describe an enantioselective carbonylation reaction using a high-valent palladium catalysis strategy and employing a chiral sulfoxide phosphine (SOP) ligand. This double aminocarbonylation reaction begins with the formation of a carbamoylpalladium(II) species, which undergoes enantioselective oxidative addition with a cyclic diaryliodonium salt to generate a palladium(IV) intermediate, followed by a second CO insertion and reductive elimination. The mechanism has been illustrated with experimental and computational studies.

Synthesis of Tribenzo[b,d,f]azepines via Palladium-Catalyzed Annulation Reaction of 2-Iodobiphenyls with 2-Halogenoanilines.

A palladium-catalyzed annulation reaction of 2-iodobiphenyls with 2-halogenoanilines has been developed. A variety of 2-iodobiphenyls and 2-halogenoanilines can undergo this transformation. Diversified tribenzo[b,d,f]azepine derivatives can be synthesized in moderate to excellent yields according to this method.

Synthesis and Evaluation of a Series of New Bulleyaconitine A Derivatives as Analgesics.

As a nonaddictive analgesic widely used in clinics, the LD50 of bulleyaconitine A is just only 0.92 mg/kg, which exhibits obvious toxicity. Therefore, 31 new non-natural C19-diterpenoid alkaloids (2a-w, 2'a-e, 3, 4a, and 4b) were designed and synthesized from bulleyaconitine A to develop nonaddictive analgesics with low toxicity. The chemical structures were characterized by 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) spectra. The analgesic activities were evaluated by a hot plate test in mice. At the dosage of 10 mg/kg, six compounds (2d, 2j, 2k, 2m, 2t, 2w) exhibited good analgesic activities (increased pain threshold >100%) with a long duration. Among them, 2w showed the best analgesic activity and the longest duration. Its pain threshold reached 166.35% in 15 min, peaked at 30 min (182.35%), and remained 82.59% even at 60 min.

Palladium-Catalyzed Synthesis and Anticancer Activity of Paclitaxel-Dehydroepiandrosterone Hybrids.

According to the activity-structure relationship of the C-13 side chain in paclitaxel or docetaxel, eighteen novel paclitaxel-dehydroepiandrosterone (DHEA) hybrids were designed and synthesized by Pd(II)-catalyzed Suzuki-Miyaura cross-coupling of 17-trifluoromethanesulfonic enolate-DHEA with different aryl boronic acids. The in vitro anticancer activity of the hybrids against a human liver cancer cell line (HepG-2) was evaluated by MTT assay, showing that most of these hybrids possessed moderate antiproliferative activity against the HepG-2 cancer cell line. Among these hybrids, three ones (7b, 7g, and 7i) with ortho-substituents in the phenyl group of the D-ring of DHEA analogues exhibited moderate anticancer activity. The optimal compound 7i showed superior anticancer activity against the HepG-2 cell line with an IC50 value of 26.39 µM.

Natural products as important tyrosine kinase inhibitors.

As an important source of drugs, natural products play an important role in the discovery and development of new drugs. More than 60% of anti-tumor drugs are closely related to natural products. At the same time, as the main cause of tumors, the abnormal activity of tyrosine kinase has become an important target for clinical treatment. Although, small molecule targeted drugs dominate the cancer treatment. Natural active products are driving the development of new tyrosine kinase inhibitors with their unique mode of action and molecular structure diversity. Obtaining new chemical entities with tyrosine kinase inhibitory activity from natural active products will bring new breakthroughs in the research of anticancer drugs. In this paper, different tyrosine kinases are mainly classified as targets, and natural products and derivatives which have been found to inhibit tyrosine kinase activity have been described. It is hoped that by analyzing the different aspects of the source, structural characteristics, mechanism of action and biological activity of these natural products, we will find new members that can be developed into drugs and promote the development of anti-tumor drugs.

Hydroxycinnamoylmalated flavone C-glycosides from Lemna japonica.

Three previously undescribed flavone C-glycosides (1-3), along with seven known ones (4-10), were isolated and characterized from the smallest flowering aquatic plant, Lemna japonica. On the basis of spectroscopic analysis and alkaline hydrolysis, compounds 1-3 were identified to be luteolin 6-C-(2″-O-trans-caffeoyl-d-malate)-ß-glucoside (1), apigenin 6-C-(2″-O-trans-caffeoyl-d-malate)-ß-glucoside (2), and luteolin 6-C-(2″-O-trans-coumaroyl-d-malate)-ß-glucoside (3). Compounds 1-3 are characteristic of a trans-coumaroyl-d-malate or trans-caffeoyl-d-malate linked to C-2″ of the glucose, which was reported for the first time. Compounds 1-3 exhibited weak cytotoxicity against HepG-2, SW-620, and A-549 cell lines, with IC50 values between 42.5 and 19.2µg/ml, and moderate antioxidant activity. Meanwhile compound 3 displayed moderate nematocidal activity with an EC50 value of 1.56mg/ml.

Cytotoxic triterpenoid saponins from Clematis tangutica.

Eight previously undescribed oleanane-type triterpenoid saponins, clematangoticosides A-H, together with eight known saponins, were isolated from the whole plants of Clematis tangutica (Maxim.) Korsh. Their structures were elucidated by extensive spectroscopic analysis, in combination with chemical methods (acid hydrolysis and mild alkaline hydrolysis). Clematangoticosides D-G were found to be unusual 23, 28-bidesmosidic glycosides. The cytotoxic activities of all of the isolated saponins were evaluated against the four human cancer cell lines SGC-7901, HepG2, HL-60 and U251MG. Clematoside S, sapindoside B, kalopanax saponin A, and koelreuteria saponin A exhibited cytotoxicity against all of the test cancer cell lines with IC50 values in the range of 1.88-27.20 µM, while clematangoticoside D and F showed selective cytotoxicity against SGC-7901 with IC50 values of 24.22 and 21.35 µM, respectively.

[Chemical Constituents from Przewalskia tangutica].

Objective: To study the Chemical constituents from Przewalskia tangutica. Methods: The compounds were isolated and identified from n-butanol extract of Przewalskia tangutica by various chromatographic and spectral techniques. Results: Twelve polar compounds were isolated and identified as scopolin( 1),fabiatrin( 2),rutin( 3),queroetin-3-O-rutinoside-7-O-ß-D-glucopyranoside( 4),protocatechuate( 5),vanillic acid( 6),thymine( 7),uracil( 8),cytosine( 9),adenine( 10),uridine( 11) and adenosine( 12). Conclusion: Compounds 3 ~ 5,8 ~ 12 are obtained from Przewalskia tangutica for the first time.

Untargeted analysis of sesquiterpene pyridine alkaloids from the dried roots of Tripterygium wilfordii using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

RATIONALE: Sesquiterpene pyridine alkaloids are a large group of highly oxygenated sesquiterpenoids that have attracted attention in the fields of medicine because of their significant biological activities. METHODS: Reference compounds including 14 sesquiterpene pyridine alkaloids and one dihydroagarofuran ester were analyzed by collision-induced dissociation tandem mass spectrometry (CID-MS/MS). A high-performance liquid chromatography/electrospray ionization (HPLC/ESI)-MS/MS method at two collision energies was adopted to investigate the botanical extracts of Tripterygium wilfordii. RESULTS: For 15 reference compounds, in the high mass range, the product ions were formed by the loss of side chains or H2 O. In the low mass range, the high-abundance product ions at m/z 206, 204, or 194 were the characteristic ions of the pyridine moiety. The characteristic product ion at m/z 310 was formed through an ion-neutral complex intermediate. Fifty-four sesquiterpenoid derivatives, including 50 sesquiterpene pyridine alkaloids, were identified or tentatively characterized in botanical extracts of T. wilfordii based on their elemental constituents, characteristic fragmentation patterns, and the major product ion profiles of the reference compounds ascertained with HPLC/ESI-MS/MS at two collision energies. It seems that isocratic energy was appropriate for the untargeted analysis of compounds with molecular weights exceeding 800 Da, whereas a linear gradient energy vs molecular weight was suitable for those compounds with molecular weights below 800 Da. CONCLUSIONS: The HPLC/ESI-MS/MS method, combining characteristic fragmentation patterns and the profiles of the product ions generated at different collision energies, is an effective technique for characterizing untargeted compounds.

Isochaetomium A2, a new bis(naphthodihydropyran-4-one) with antimicrobial and immunological activities from fungus Chaetomium microcephalum.

Isochaetomium A2 (1), a new bis(naphthodihydropyran-4-one), along with chaetochromins A (2) and B (3), was isolated from the solid-state fermented rice culture of Chaetomium microcephalum. The structure of compound 1 was elucidated on the basis of 1D and 2D NMR spectral data, and the relative configuration was confirmed by CD spectrum. Compounds 1-3 possessed significant antimicrobial activity against Escherichia coli 1.044, Staphylococcus aureus 1.252, and Bacillus subtilis 1.079. Moreover, compounds 1-3 showed obvious inhibitory effects on mouse spleen cell proliferation with successive IC50 values of 0.52, 0.19, and 0.24 µM.

Evaluation of relative isotopic abundance measurements in a quadrupole time-of-flight mass spectrometer for elemental composition determination of natural products in traditional Chinese medicine.

The relative isotopic abundance (RIA) measurement errors of a quadrupole time-of-flight (Q-ToF) instrument incorporating analog-to-digital converter detectors were systemically evaluated by stochastically collecting about 200 data in positive ion mass spectrometry (MS) mode. Errors varied with peak intensities at definite spectral acquisition rates but were very close, even if peak intensities changed sharply at different spectral acquisition rates with the same concentration. Intensity thresholds were systematically defined at 1 Hz of spectral acquisition rates. RIA measurement errors were also evaluated using peak area. It seemed that peak area was better adapted for the high-intensity ions while peak intensity was suited for very low-intensity ions. Several known compounds were selected for RIA measurements for product ions in tandem mass spectropmetry (MS/MS) mode. An extract of a representative traditional Chinese medicinal, Paederia scandens was analyzed with high-performance liquid chromatography-electrospray ionization-QToF-MS/MS. The unique elemental compositions of some compounds could not be identified even with exact masses and MS/MS spectra of measured and reference compounds. RIA errors, especially of (M+2)M(-1), provided vital information for determining the elemental composition.

Analysis of mexicanolide- and phragmalin-type limonoids from Heynea trijuga using high-performance liquid chromatography/electrospray tandem mass spectrometry.

RATIONALE: Limonoids, a class of tetranortriterpenoids, exhibit various biological effects, including acting as potent antifeedants and insect growth-regulators against various pests. The analysis of phragmalin- and mexicanolide-type limonoids by collision-induced dissociation tandem mass spectrometry (CID-MS/MS) has not been reported. METHODS: A high-performance liquid chromatography/electrospray ionization (HPLC/ESI)-MS/MS method was developed to investigate the fragmentation patterns of [M+NH4 ](+) ions for nine reference phragmalin- and mexicanolide-type limonoids. The method was also used in the identification of limonoid compounds in botanic extracts of Heynea trijuga. RESULTS: The losses of side chains and the furan part were the major fragmentation patterns. However, there was variation in the relative abundances of product ions resulting from the same fragmentation pathways. A total of 89 phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga were detected and 50 of these compounds were identified or tentatively characterized based on elemental constituents, fragmentation pathways, and the profile of the major product ions of reference compounds. In addition, the isomers could be tentatively distinguished. CONCLUSIONS: An HPLC/ESI-MS/MS method was developed and could be used to simultaneously identify and screen phragmalin- and mexicanolide-type limonoids in botanic extracts of Heynea trijuga.

Analysis of iridoid glucosides from Paederia scandens using HPLC-ESI-MS/MS.

Iridoid glycosides are an important class of natural products and have many biological activities. Iridoid glucosides in an extract of the plant species Paederia scandens were investigated using reversed-phase high performance liquid chromatography and electrospray quadrupole time-of-flight-type tandem mass spectrometry. The elemental composition of most of the compounds was determined by accurate mass and relative isotopic abundance (RIA) measurements. In positive ion mode, the fragmentation of [M+NH4](+) precursor ions was carried out using low energy collision-induced electrospray ionization tandem spectrometry. The neutral losses of NH3, H2O, Glc, and the side chain of the iridoid moiety were the main fragmentation patterns observed. For simple iridoid glycosides, the main differences were related to the side chains. Fragmentation of the [M-H](-)precursor ions was achieved for the compounds possibly having phenolic acid group. The connection order of the iridoid, sugar, and phenolic acid moieties, and the linkage of the 6-OH group of the sugar to the phenolic acid were unambiguously confirmed using a combination of MS/MS spectra in both positive and negative ion modes, and our previous work. For some trace dimeric iridoid glucosides, the connection order between the asperuloside and paederoside moieties was determined by the characteristic product ions; this was supported by D-labeling experiments. A total of 24 iridoid glucosides, including 14 new species, were identified or tentatively characterized based on exact mass, RIA values, tandem mass spectra, and D-labeling experiments.

Analyses of the iridoid glucoside dimers in Paederia scandens using HPLC-ESI-MS/MS.

INTRODUCTION: Many dimers consisting of structurally similar monomers are difficult to be identified even using NMR. Rapid structural identification of iridoid glycoside dimers, especially isomeric dimers in a complicated matrix, remains desirable. OBJECTIVE: To develop a rapid, sensitive analytical method for structural elucidation of trace iridoid glycoside isomers in a complicated extract. METHODS: Three isomeric iridoid glucoside dimers, paederoscandoside, saprosmoside E and saprosmoside D, were isolated and further analysed by electrospray ionisation quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS) in positive-ion mode. Energy-resolved mass spectrometry (ERMS) was used to provide information on the relative intensity of ions versus collision energy. The crude extract of Paederia scandens was analysed by HPLC-ESI-MS/MS. RESULTS: The relative abundance of product ions in the MS/MS spectra from ammonium adduct ions varied greatly for the three isomers. The energy-resolved experiments enhanced differences among the three isomers. A total of 13 iridoid glucoside dimers (three groups of isomers) in the extract of P. scandens were identified or tentatively characterised by using HPLC-ESI-QTOF based on the tandem mass spectra of references. CONCLUSION: Linkage sites between different hydroxyl groups on the sugar and carboxyl groups for the three groups of isomers are confirmed. The reason for fragmentation differences might be that cleavage of the glycosidic bond accompanies the active H in vicinal hydroxyl rearrangement. The MS method is a useful tool for the analysis of isomers, especially trace isomers in a complicated extract.