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Air Flow-Assisted Ionization Imaging Mass Spectrometry Method for Easy Whole-Body Molecular Imaging under Ambient Conditions

Whole-body molecular imaging is able to directly map spatial distribution of molecules and monitor its biotransformation in intact biological tissue sections. Imaging mass spectrometry (IMS), a label-free molecular imaging method, can be used to image multiple molecules in a single measurement with high specificity. Herein, a novel easy-to-implement, whole-body IMS method was developed with air flow-assisted ionization in a desorption electrospray ionization mode. The developed IMS method can effectively image molecules in a large whole-body section in open air without sample pretreatment, such as chemical labeling, section division, or matrix deposition. Moreover, the signal levels were improved, and the spatial assignment errors were eliminated; thus, high-quality whole-body images were obtained. With this novel IMS method, in situ mapping analysis of molecules was performed in adult rat sections with picomolar sensitivity under ambient conditions, and the dynamic information of molecule distribution and its biotransformation was provided to uncover molecular events at the whole-animal level. A global view of the differential distribution of an anticancer agent and its metabolites was simultaneously acquired in whole-body rat and model mouse bearing neuroglioma along the administration time. The obtained drug distribution provided rich information for identifying the targeted organs and predicting possible tumor spectrum, pharmacological activity, and potential toxicity of drug candidates.

Anti-inflammatory coumarin and benzocoumarin derivatives from Murraya alata.

Two new rare 8-methylbenzo[h]coumarins, muralatins A and B (1, 2), nine new C-8-substituted coumarins, muralatins C-K (3-11), and 22 known analogues (12-33) were isolated from the leaves of Murraya alata. The absolute configurations of compounds 5, 11, 23, 24, 27, 30, and 33 were assigned via comparison of their specific rotations, by Moshers method, and by single-crystal X-ray diffraction and electronic circular dichroism (ECD) data of the in situ formed transition metal complexes. A putative biosynthesis pathway to 1 and 2 is proposed, and the chemical synthesis of 1 was accomplished through electrocyclization of 5,7-dimethoxy-8-[(Z)-3-methylbut-1,3-dienyl)]coumarin (12). Compounds 1, 2, 8, 12, and 31 showed inhibition of nitric oxide production in lipopolysaccharide-induced RAW 264.7 macrophages with IC50 values of 6.0-14.5 μM.

Lycojaponicumins D and E: Two New Alkaloids from Lycopodium japonicum

Two new alkaloids, lycojaponicumins D (1) and E (2), were isolated from the club moss Lycopodium japonicum. Their structures were elucidated by spectroscopic methods, calculated ECD, CD experiments and X-ray diffraction analysis. Lycojaponicumin D (1) possesses an unprecedented 5/7/6/6 tetracyclic skeleton formed by an unusual C3-C13 linkage, which is first reported in Lycopodium alkaloids. The plausible biogenetic pathway of 1 is proposed.

Mollolide A, a diterpenoid with a new 1,10:2,3-disecograyanane skeleton from the roots of Rhododendron molle.

Mollolide A (1), a diterpenoid featuring a new 1,10:2,3-disecograyanane skeleton, was isolated from the roots of Rhododendron molle. Its structure was elucidated through extensive MS, IR, and NMR spectroscopy analyses. The absolute configuration was determined by single-crystal X-ray diffraction of its p-bromobenzoate derivative (1b). Compound 1 exhibits a significant analgesic effect at a dose of 20 mg/kg and antiviral activity against the Coxsackie B3 virus with an IC50 value of 27.7 μM.

Lysidicins F−H, Three New Phloroglucinols from Lysidice rhodostegia

Three new phloroglucinols, named lysidicins F-H (1-3), were isolated from the roots of Lysidice rhodostegia. These compounds have a unprecedented benzyl benzo[b]furo[3,2-d]furan skeleton, and lysidicin F (1) is the first example of natural product with trans-fused furan rings. Their structures were established on the basis of extensive spectroscopic analysis, and the absolute configurations of them were determined by computational methods. A possible biosynthetic pathway for 1-3 was also postulated.

Cytotoxic cardenolides from the stems of Periploca forrestii.

Six new cardenolides, periforosides D-E (1-2), periforgenin C (3) and periforosides F-H (4-6), as well as 10 previously identified cardenolides (7-16) were isolated from the ethanol extract of the stems of Periploca forrestii. The structures of the new compounds were determined using extensive spectroscopic analyses including HRESI-MS, 1D and 2D NMR data. Evaluation of the cytotoxic activity of all the isolated compounds in five different human cancer cell lines indicated that compounds 2-6, 8, 9 and 12-16 have potent activity.

Synthesis, biological evaluation and mechanism studies of deoxytylophorinine and its derivatives as potential anticancer agents.

Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression.

Identification of cardiac glycosides in fractions from Periploca forrestii by high-performance liquid chromatography/diode-array detection/electrospray ionization multi-stage tandem mass spectrometry and liquid chromatography/nuclear magnetic resonance

Cardiac glycosides are a class of naturally occurring compounds that are characterized by some interesting biological activities and are widely distributed in the plant kingdom and can also be found in some animals. There is an interest in the chemical characterization of these molecules due to their toxicity and their use in medicines. In the study reported here, a combination of electrospray ionization tandem mass spectrometry with high-performance liquid chromatography equipped with diode-array detector (HPLC-DAD/ESI-MS(n)), and hyphenation to both liquid chromatography and nuclear magnetic resonance spectroscopy (HPLC/NMR) were utilized for the on-line analyses of cardiac glycosides from Periploca forrestii. The fragmentation patterns and (1)H NMR spectra of nine isolated cardiac glycosides were investigated; their fragmentation rules and (1)H NMR spectral characteristics were summarized and applied to the structural identification of similar constituents in fractions from P. forrestii. As a result, a total of nine trace cardiac glycosides were tentatively determined by analyses of accurate molecular masses, representative fragment ions and characteristic (1)H NMR signals provided by HPLC/high-resolution mass spectrometry (HRMS), HPLC-DAD/ESI-MS(n) and HPLC/(1)H NMR experiments, respectively. Of these, eight (2-9) are new compounds and one (1) is reported from P. forrestii for the first time. Results of the present study can benefit the rapid identification and targeted isolation of new cardiac glycosides from crude plant extracts.

Antinociceptive Grayanoids from the Roots of Rhododendron molle.

Nine new grayanoids (1-9), together with 11 known compounds, were isolated from the roots of Rhododendron molle. The structures of the new compounds (1-9) were determined on the basis of spectroscopic analysis, including HRESIMS, and 1D and 2D NMR data. Compounds 4, 6, 12, and 14-20 showed significant antinociceptive activities in an acetic acid-induced writhing test. In particular, 14 and 15 were found to be more potent than morphine for both acute and inflammatory pain models and 100-fold more potent than gabapentin in a diabetic neuropathic pain model.

Structures and absolute configurations of penicillactones A-C from an endophytic microorganism, Penicillium dangeardii Pitt.

Penicillactones A-C (1-3) are structurally related natural products with a spirocyclic anhydride structure and were isolated from the endophytic fungus Penicillium dangeardii Pitt. Penicillactones B and C showed inhibition of the release of β-glucuronidase from polymorphonuclear leukocytes with ED50 values of 2.58 and 1.57 μM. A 2D INADEQUATE experiment of 1 was performed at natural abundance to confirm the arrangement of its carbon skeleton. The configurations of 1-3 were established through extensive NMR spectroscopic analysis, selective structural modifications, and CD analysis.