鹊肾树心材的化学成分及体外抗菌活性研究

本文研究鹊肾树Streblus asper心材的乙酸乙酯部分化学成分及体外抗菌活性.运用正相硅胶柱色谱层析,反相C-18柱色谱层析和Sephadex LH-20分高、纯化,最终得到8个化合物,经波谱解析并结合理化鉴定确定化合物结构为:银杏双黄酮(1)、异黄酮-4′-甲氧基-7-α-L-鼠李糖-(1→6)-β-D-葡萄糖(2)、鼠李柠檬素-3-O-β-D-半乳糖苷(3)、β-香树脂酮(4)、β-谷甾醇(5)、香革酸(6)、山俞酸(7)、二十六烷酸(8).除化合物5外,均为首次从该植物中提取到.此外研究了化合物1-4的抗菌活性,实验表明化合物2具有一定的抑菌活性.     

Three Sesquiterpenoid Dimers from Chloranthus japonicus: Absolute Configuration of Chlorahololide A and Related Compounds

A novel sesquiterpenoid dimer, named multistalide C ( 1 ), together with two known congeners, shizukaols C ( 2 ) and D ( 3 ), was isolated from the whole plant of Chloranthus japonicus Sieb. The structures of compounds 1 , 2 , 3 were elucidated by extensive HR‐ESI‐MS, 1D, and 2D NMR spectroscopic analysis. Compounds 1 , 2 , 3 exhibited significant toxic effects on brine shrimp larvae (Artemia salina). The absolute configuration of 1 was established by CD/TDDFT calculations. The related compound chlorahololide A was also reinvestigated. The previous assignment of the absolute configuration of chlorahololide A and several related sesquiterpenoid dimers, based on an incorrect application of the exciton chirality method, is criticized. Chirality 28:158–163, 2015. © 2015 Wiley Periodicals, Inc.     

New Acetohydrazides Incorporating 2‐Oxoindoline and 4‐Oxoquinazoline: Synthesis and Evaluation of Cytotoxicity and Caspase Activation Activity

In our search for new small molecules activating procaspase‐3, we have designed and synthesized a series of new acetohydrazides incorporating both 2‐oxoindoline and 4‐oxoquinazoline scaffolds. Biological evaluation showed that a number of these acetohydrazides were comparably or even more cytotoxic against three human cancer cell lines (SW620, colon cancer; PC‐3, prostate cancer; NCI?H23, lung cancer) in comparison to PAC‐1, a first procaspase‐3 activating compound, which was used as a positive control. One of those new compounds, 2‐(6‐chloro‐4‐oxoquinazolin‐3(4H)‐yl)‐N′‐[(3Z)‐5‐methyl‐2‐oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene]acetohydrazide activated the caspase‐3 activity in U937 human lymphoma cells by 5‐fold higher than the untreated control. Three of the new compounds significantly induced necrosis and apoptosis in U937 cells.     

Quinazoline‐Based Hydroxamic Acids: Design,Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N‐hydroxybenzamides incorporating quinazoline heterocycles ( 4a  –  4i , 6a  –  6i ). Bioevaluation showed that these quinazoline‐based hydroxamic acids and N‐hydroxybenzamides were potently cytotoxic against three human cancer cell lines (SW620, colon; PC‐3, prostate; NCI‐H23, lung). In term of cytotoxicity, several compounds, e.g., 4g , 4c , 4g  –  4i , 6c , and 6h , displayed from 5‐ up to 10‐fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDACs with IC₅₀ values in sub‐micromolar range. Some compounds, e.g., 4g , 6c , 6e , and 6h , were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities higher than that of SAHA. Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity (ADMET) suggested that compounds 4g , 6c , and 6g , while showing potent HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.     

Crystal Structures of Penicillin-Binding Proteins 4 and 5 from Haemophilus influenzae

We have determined high-resolution apo crystal structures of two low molecular weight penicillin-binding proteins (PBPs), PBP4 and PBP5, from Haemophilus influenzae, one of the most frequently found pathogens in the upper respiratory tract of children. Novel β-lactams with notable antimicrobial activity have been designed, and crystal structures of PBP4 complexed with ampicillin and two of the novel molecules have also been determined. Comparing the apo form with those of the complexes, we find that the drugs disturb the PBP4 structure and weaken X-ray diffraction, to very different extents. PBP4 has recently been shown to act as a sensor of the presence of penicillins in Pseudomonas aeruginosa, and our models offer a clue to the structural basis for this effect. Covalently attached penicillins press against a phenylalanine residue near the active site and disturb the deacylation step. The ready inhibition of PBP4 by β-lactams compared to PBP5 also appears to be related to the weaker interactions holding key residues in a catalytically competent position.     

Mineral Content,Antioxidant Activity and Essential Oil of Allophylus edulis (A. St.-Hil., A. Juss. & Cambess.) Radlk. Leaves: Plant from South American Biodiversity

Allophylus edulis (A. St.-Hil., A. Juss. & Cambess.) Radlk. (Sapindaceae) is an edible plant from the South American biodiversity that is a potential source of bioactive compounds. The mineral content and antioxidant activity of Allophylus edulis leaves were investigated, as well as the composition and the antioxidant activity of the essential oil. The mineral content was determined by ICP – OES and the antioxidant assays were assessed by ABTS, DPPH and FRAP. The essential oil was obtained by hydrodistillation and analyzed by GC/MS. Calcium, potassium, phosphorus, sulfur, and magnesium were the main minerals found in A. edulis leaves. Of the toxic metals that were present, a low level of aluminum was detected. The essential oil of A. edulis has (E)-nerolidol as major compound and both, the leaves, and the essential oil isolated from the leaves have antioxidant potential. These findings could provide a framework for developing new food and non-food products with A. edulis leaves.     

Isolation,Stereochemical Study,and Antioxidant Activity of Benzofuranone Derivatives from a Mangrove‐derived Fungus Eurotium rubrum MA‐150

Enantiomers of a 2‐benzofuran‐1(3H)‐one derivative [(–)‐ 1 and (+)‐ 1 ] and four known analogs ( 2 , 3 , 4 , 5 ) were isolated and identified from the culture extract of Eurotium rubrum MA–150, a fungus obtained from the mangrove‐derived rizospheric soil. Their structures were established by detailed interpretation of nuclear magnetic resonance (NMR) data and the structure of (±)‐ 1 was confirmed by single‐crystal X‐ray diffraction analysis. The absolute configuration of the enantiomers (–)‐ 1 and (+)‐ 1 was determined by means of online high‐performance liquid chromatography – electronic circular dichroism (HPLC‐ECD) measurements and time‐dependent Density Functional Theory – electronic circular dichroism (TDDFT‐ECD) calculations. Compounds (±)‐ 1 as well as 2 and 3 exhibited potent DPPH radical scavenging activities with IC₅₀ values of 1.23, 2.26, and 3.99 μg/mL, respectively. Chirality 28:581–584, 2016. © 2016 Wiley Periodicals, Inc.     

Apo and Calcium-Bound Crystal Structures of Cytoskeletal Protein Alpha-14 Giardin (Annexin E1) from the Intestinal Protozoan Parasite Giardia lamblia

Alpha-14 giardin (annexin E1), a member of the alpha giardin family of annexins, has been shown to localize to the flagella of the intestinal protozoan parasite Giardia lamblia. Alpha giardins show a common ancestry with the annexins, a family of proteins most of which bind to phospholipids and cellular membranes in a Ca²⁺-dependent manner and are implicated in numerous membrane-related processes including cytoskeletal rearrangements and membrane organization. It has been proposed that alpha-14 giardin may play a significant role during the cytoskeletal rearrangement during differentiation of Giardia. To gain a better understanding of alpha-14 giardin's mode of action and its biological role, we have determined the three-dimensional structure of alpha-14 giardin and its phospholipid-binding properties. Here, we report the apo crystal structure of alpha-14 giardin determined in two different crystal forms as well as the Ca²⁺-bound crystal structure of alpha-14 giardin, refined to 1.9, 1.6 and 1.65 Å, respectively. Although the overall fold of alpha-14 giardin is similar to that of alpha-11 giardin, multiwavelength anomalous dispersion phasing was required to solve the alpha-14 giardin structure, indicating significant structural differences between these two members of the alpha giardin family. Unlike most annexin structures, which typically possess N-terminal domains, alpha-14 giardin is composed of only a core domain, followed by a C-terminal extension that may serve as a ligand for binding to cytoskeletal protein partners in Giardia. In the Ca²⁺-bound structure we detected five bound calcium ions, one of which is a novel, highly coordinated calcium-binding site not previously observed in annexin structures. This novel high-affinity calcium-binding site is composed of seven protein donor groups, a feature rarely observed in crystal structures. In addition, phospholipid-binding assays suggest that alpha-14 giardin exhibits calcium-dependent binding to phospholipids that coordinate cytoskeletal disassembly/assembly during differentiation of the parasite.     

Intercalating Nucleic Acids: The Influence of Linker Length and Intercalator Type on Their Duplex Stabilities

Six new examples of intercalating nucleic acids were synthesized in order to evaluate the dependence of the length of the linker between oligo and intercalator on the thermal stability of their corresponding duplexes and triplexes.     

GABA transporters mediate glycine release from cerebellum nerve endings: roles of Ca(2+)channels, mitochondrial Na(+)/Ca(2+) exchangers, vesicular GABA/glycine transporters and anion channels

GABA transporters accumulate GABA to inactivate or reutilize it. Transporter-mediated GABA release can also occur. Recent findings indicate that GABA transporters can perform additional functions. We investigated how activation of GABA transporters can mediate release of glycine. Nerve endings purified from mouse cerebellum were prelabeled with [(3)H]glycine in presence of the glycine GlyT1 transporter inhibitor NFPS to label selectively GlyT2-bearing terminals. GABA was added under superfusion conditions and the mechanisms of the GABA-evoked [(3)H]glycine release were characterized. GABA stimulated [(3)H]glycine release in a concentration-dependent manner (EC(50) = 8.26 μM). The GABA-evoked release was insensitive to GABA(A) and GABA(B) receptor antagonists, but it was abolished by GABA transporter inhibitors. About 25% of the evoked release was dependent on external Ca(2+) entering the nerve terminals through VSCCs sensitive to ω-conotoxins. The external Ca(2+)-independent release involved mitochondrial Ca(2+), as it was prevented by the Na(+)/Ca(2+) exchanger inhibitor CGP37157. The GABA uptake-mediated increases in cytosolic Ca(2+) did not trigger exocytotic release because the [(3)H]glycine efflux was insensitive to clostridial toxins. Bafilomycin inhibited the evoked release likely because it reduced vesicular storage of [(3)H]glycine so that less [(3)H]glycine can become cytosolic when GABA taken up exchanges with [(3)H]glycine at the vesicular inhibitory amino acid transporters shared by the two amino acids. The GABA-evoked [(3)H]glycine efflux could be prevented by niflumic acid or NPPB indicating that the evoked release occurred essentially by permeation through anion channels. In conclusion, GABA uptake into GlyT2-bearing cerebellar nerve endings triggered glycine release which occurred essentially by permeation through Ca(2+)-dependent anion channels. Glial GABA release mediated by anion channels was proposed to underlie tonic inhibition in the cerebellum; the present results suggest that glycine release by neuronal anion channels also might contribute to tonic inhibition.