Bis-Spiro-Oxetane and Bis-Spiro-Tetrahydrofuran Pyrroline Nitroxide Radicals: Synthesis and Electron Spin Relaxation Studies.

Synthesis of bis-spiro-oxetane and bis-spiro-tetrahydrofuran pyrroline nitroxide radicals relies on the Mitsunobu reaction-mediated double cyclizations of N-Boc protected pyrroline tetraols. Structures of the nitroxide radicals are supported by X-ray crystallography. In a trehalose/sucrose matrix at room temperature, the bis-spiro-oxetane nitroxide radical possesses electron spin coherence time, Tm ≈ 0.7 µs. The observed enhanced Tm is most likely associated with strong hydrogen bonding of oxetane moieties to the trehalose/sucrose matrix.

Truncated Cross Effect Dynamic Nuclear Polarization: An Overhauser Effect Doppelgänger.

The discovery of a truncated cross-effect (CE) in dynamic nuclear polarization (DNP) NMR that has the features of an Overhauser-effect DNP (OE-DNP) is reported here. The apparent OE-DNP, where minimal µw power achieved optimum enhancement, was observed when doping Trityl-OX063 with a pyrroline nitroxide radical that possesses electron-withdrawing tetracarboxylate substituents (tetracarboxylate-ester-pyrroline or TCP) in vitrified water/glycerol at 6.9 T and at 3.3 to 85 K, in apparent contradiction to expectations. While the observations are fully consistent with OE-DNP, we discover that a truncated cross-effect ( tCE) is the underlying mechanism, owing to TCP's shortened T1e. We take this observation as a guideline and demonstrate that a crossover from CE to tCE can be replicated by simulating the CE of a narrow-line (Trityl-OX063) and a broad-line (TCP) radical pair, with a significantly shortened T1e of the broad-line radical.

Reduction kinetics and electrochemistry of tetracarboxylate nitroxides.

Tetracarboxylate pyrroline nitroxides undergo very fast reduction with ascorbate/glutathione (GSH), with second-order rate constants that are five orders of magnitude greater than those for gem-diethyl pyrroline nitroxides. For tetracarboxylate nitroxides, the electrochemical reduction potentials, measured by square wave voltammetry, are much less negative (by about 0.8 V), compared with the corresponding gem-diethyl nitroxides, while the oxidation potentials become more positive (by about 0.7 V). Electrochemical potentials correlate well via simple regressions with field/inductive parameters such as Swain/Lupton F-parameters (and/or Charton σI-parameters). Rates of reduction with ascorbate/GSH similarly correlate well for four pyrroline nitroxides, except for the slowest reducing gem-diethyl nitroxide. These results suggest that the electron withdrawing groups adjacent to the nitroxide moiety have a strong accelerating impact on the reduction rates, and thus they are not suitable for the design of hydrophilic nitroxides for in vivo applications.

Synthesis and Electron Spin Relaxation of Tetracarboxylate Pyrroline Nitroxides.

We report the design, synthesis, and electron spin relaxation properties of hydrophilic tetracarboxylate ester pyrroline nitroxides 1 and 2, which serve as models in the search for new spin labels for DEER distance measurement at room temperature. The nitroxides are designed to have the methyl groups further away from the N-O spin site to decrease the inequivalent couplings of the unpaired electron to the methyl protons that shorten Tm at T > 70 K in currently used labels. The key step in the synthesis of 1 and 2 is the reaction of the dianion of pyrrole-1,2,5-tricarboxylic acid tert-butyl ester dimethyl ester with electrophiles such as methyl chloroformate and methyl bromoacetate. Structures of 1 and 2 are confirmed by X-ray crystallography. Studies of electron spin relaxation rates in rigid trehalose/sucrose matrices reveal approximately temperature independent values of 1/Tm for 1 and 2 up to about 160 K and modest temperature dependence up to 295 K, demonstrating that increasing the distance between the nitroxide moiety and methyl groups is effective in lengthening Tm at T > 70 K.

Alkaloids with Different Carbon Units from Myrioneuron faberi.

Three new Myrioneuron alkaloids, myrifamines A-C (1-3), with unique skeletons were isolated from Myrioneuron faberi. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis, and the stereochemistry of the other two alkaloids was determined using a combination of ROESY experiments and calculated and experimental electronic circular dichroism spectra. Myrifamine C (3) is the first example of a symmetric dimer among the Myrioneuron alkaloids. Known alkaloids myrionamide (4) and schoberine (5) were also isolated, and experimental NMR and X-ray diffraction data suggest their structural revision. Compound 2 showed significant inhibitory activity toward the hepatitis C virus in vitro, with a therapeutic index (CC50/EC50) greater than 108.7.

Discovery of Imidazo[1,2-α][1,8]naphthyridine Derivatives as Potential HCV Entry Inhibitor.

RO8191 represents a newly discovered small-molecule IFN-like agent that displays potent anti-HCV activity. With it as lead, a series of compounds bearing an imidazo[1,2-α][1,8]naphthyridine core and an amide bond-linked side chain were designed and synthesized. These compounds were evaluated on HCV cell culture system (HCVcc-hRluc-JFH1), and some of them exhibited remarkable anti-HCV activity (EC50 = 0.017-0.159 µM) and low toxicity (CC50 > 25 µM). Moreover, it was revealed that these newly identified anti-HCV agents exert their antiviral effect through a distinct mechanism of action from that of RO8191 by targeting the viral entry process. Thus, our study provides a starting point for the development of potential HCV entry inhibitor.

Design and synthesis of imidazo[1,2-α][1,8]naphthyridine derivatives as anti-HCV agents via direct C-H arylation.

RO8191 represents a newly identified small-molecule IFN-α-substitute, which displays potent anti-HCV activity. In this communication, we reported the design and synthesis of two series of imidazo[1,2-α][1,8]naphthyridine derivatives, as RO8191 analogues, via a direct C-H arylation approach. Notably, by adjusting the reaction conditions, we could achieve the two series of analogues via regioselective single- and double-arylations, respectively. The anti-HCV activities of the synthesized compounds were evaluated within the HCV cell culture system, and the preliminary results showed that some of them displayed promising anti-HCV activities.

Myrifabine, the first dimeric Myrioneuron alkaloid from Myrioneuron faberi.

One Myrioneuron alkaloid, myrifabine (1), the first example of a dimer with 12 chiral centers embraced in a decacyclic novel skeleton, was isolated from Myrioneuron faberi . Its structure was elucidated by spectroscopic data and single-crystal X-ray diffraction. The antimicrobial and cytotoxic activities of 1 were evaluated in vitro.

Bioinspired total synthesis of katsumadain A by organocatalytic enantioselective 1,4-conjugate addition.

Katsumadain A, a naturally occurring influenza virus neuraminidase (NA) inhibitor, was synthesized by using a bioinspired, organocatalytic enantioselective 1,4-conjugate addition of styryl-2-pyranone with cinnamaldehyde, followed by a tandem Horner-Wadsworth-Emmons/oxa Michael addition.

A new Amaryllidaceae alkaloid from the bulbs of Lycoris radiata.

AIM: To study the Amaryllidaceae alkaloids of the bulbs of Lycoris radiata. METHODS: The chemical constituents were isolated and purified by various chromatographic techniques, and the chemical structures were elucidated on the basis of spectroscopic methods. In addition, the antiviral activities of alkaloids 1-10 were evaluated using flu virus A. RESULTS: One new homolycorine-type alkaloid 2α-methoxy-6-O-ethyloduline (1), together with nine known alkaloids 2α-methoxy-6-O-methyloduline (2), trispherine (3), 8-O-demethylhomolycorine (4), homolycorine (5), 9-O-demethylhomolycorine (6), oduline (7), lycorenine (8), 6α-O-methyllycorenine (9) and O-ethyllycorenine (10) were obtained. CONCLUSION: Alkaloid 1 is a new compound, and 1-3 were major alkaloids in this plant. Alkaloids 1-3 showed weak antiviral activities against flu virus A with IC50 values of 2.06, 0.69, and 2.71 µg·mL-1 and CC50 values of 14.37, 4.79, and 80.12 µg·mL-1, respectively.

Myriberine A, a new alkaloid with an unprecedented heteropentacyclic skeleton from Myrioneuron faberi.

Myriberine A (1) possessing an unprecedented carbon skeleton was isolated from Myrioneuron faberi. The structure and absolute configuration of 1 were elucidated by a combination of spectroscopic data, X-ray crystallographic, and computational methods. Myriberine A (1) demonstrated inhibition against the hepatitis C virus (HCV) life cycle in vitro.

Daphmacromines A-J, alkaloids from Daphniphyllum macropodum.

Ten new yuzurine-type Daphniphyllum alkaloids, daphmacromines A-J (1-10), along with seven known alkaloids were isolated from the leaves and stems of Daphniphyllum macropodum. Their structures were elucidated by extensive spectroscopic techniques, including 2D NMR spectroscopy and mass spectrometry, and the structure of 1 was confirmed by single-crystal X-ray diffraction. The pesticidal and cytotoxic activities of the isolated alkaloids were evaluated in vitro against brine shrimp (Artemia salina) and five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, and SW480), respectively. This study also suggested structural revisions of oxodaphnigracine, oxodaphnigraciline, and epioxodaphnigraciline.