The Interaction of Per‐O‐Acetylated Acyclic 1‐(1‐Butylindol‐3‐yl)‐1‐deoxy‐ketoses with Silylated Uracil

The per‐O‐acetylated open chain derivatives of 1‐(1‐butylindol‐3‐yl)‐1‐deoxy‐1‐L‐sorbose and 1‐(1‐butylindol‐3‐yl)‐1‐deoxy‐L‐tagatose, which are readily available by alkaline degradation of 1‐butylascorbigen followed by acetylation, were used in a nucleoside‐type synthesis. The interaction of these ketoses derivatives with bis‐(trimethylsilyl)‐uracil yielded in each case a mixture of (E)‐2,4,5,6‐tetra‐O‐acetyl‐1‐(1‐butylindol‐3‐yl)‐1,3‐dideoxy‐3‐(uracil‐1‐yl)‐L‐xylo‐hexa‐1‐enitol and (E)‐2,4,5,6‐tetra‐O‐acetyl‐1‐(1‐butylindol‐3‐yl)‐1,3‐dideoxy‐3‐(uracil‐1‐yl)‐L‐lyxo‐hexa‐1‐enitol, which were separated by preparative HPLC. The deacetylation of each of these compounds by MeONa in MeOH produced a mixture of 1‐(1‐butylindol‐3‐yl)‐1,3‐dideoxy‐4‐O‐methyl‐3‐(uracil‐1‐yl)‐α‐L‐sorbopyranose and 1‐(1‐butylindol‐3‐yl)‐1,3‐dideoxy‐4‐O‐methyl‐3‐(uracil‐1‐yl)‐β‐D‐fructopyranose, which were also separated by HPLC, the structures were confirmed by NMR.     

New Isoprenylated 2‐Arylbenzofurans and Pancreatic Lipase Inhibitory Constituents from Artocarpus nitidus

Two new isoprenylated 2‐arylbenzofurans, artonitidin A (=(2′R)‐2′,3′‐dihydro‐2′‐(1‐hydroxy‐1‐methylethyl)‐5′,7‐bis(3‐methylbut‐2‐en‐1‐yl)‐2,4′‐bi‐1‐benzofuran‐6,6′‐diol; 1 ) and artonitidin B (=5‐[6‐hydroxy‐7‐(3‐methylbut‐2‐en‐1‐yl)‐1‐benzofuran‐2‐yl]‐4‐(3‐methylbut‐2‐en‐1‐yl)benzene‐1,3‐diol; 2 ), together with 14 known compounds, 3 – 16 , were isolated from the stems of Artocarpus nitidus Trec. The structures were elucidated by spectroscopic methods. Norartocarpin ( 3 ), cudraflavone C ( 5 ), brosimone I ( 8 ), artotonkin ( 11 ), albanin A ( 13 ), and artopetelin M ( 14 ) showed inhibitory effects on pancreatic lipase with IC₅₀ values ranging from 1.8±0.1 to 63.8±3.6 μM .     

Cytotoxic Steroidal Saponins from the Rhizomes of Tacca integrifolia

Three new steroid saponins (3β,25R)‐spirost‐5‐en‐3‐yl 6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[β‐D ‐glucopyranosyl‐(1→4)‐6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 1 ), (3β,22R,25R)‐26‐(β‐D ‐glucopyranosyloxy)‐22‐hydroxyfurost‐5‐en‐3‐yl 6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 3 ), and (3β,22R,25R)‐26‐(β‐D ‐glucopyranosyloxy)‐22‐hydroxyfurost‐5‐en‐3‐yl 6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[β‐D ‐glucopyranosyl‐(1→4)‐6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 5 ), as well as the new pregnane glycoside (3β,16β)‐3‐{[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranosyl]oxy}‐20‐oxopregn‐5‐en‐16‐yl (4R)‐5‐(β‐D ‐glucopyranosyloxy)‐4‐methylpentanoate ( 6 ), were isolated from the rhizomes of Tacca integrifolia together with two known (25R) configurated steroid saponins (3β,25R)‐spirost‐5‐en‐3‐yl 6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 2 ) and (3β,22R,25R)‐26‐(β‐D ‐glucopyranosyloxy)‐22‐methoxyfurost‐5‐en‐3‐yl 6‐deoxy‐α‐L ‐mannopyranosyl‐(1→2)‐[6‐deoxy‐α‐L ‐mannopyranosyl‐(1→3)]‐β‐D ‐glucopyranoside ( 4 ). The cytotoxic activity of the isolated compounds was evaluated in HeLa cells and showed the highest cytotoxicity value for compound 2 with an IC₅₀ of 1.2±0.4 μM . Intriguingly, while compounds 1 – 5 exhibited similar cytotoxic properties between 1.2±0.4 ( 2 ) and 4.0±0.6 μM ( 5 ), only compound 2 showed a significant microtubule‐stabilizing activity in vitro.     

Benzopyran Derivatives and an Aliphatic Compound from a Mangrove Endophytic Fungus Penicillium citrinum QJF‐22

Two new benzopyran derivatives, (2R,4S)‐5‐methoxy‐2‐methyl‐3,4‐dihydro‐2H‐1‐benzopyran‐4‐ol and (2S,4R,2′S,4′R)‐4,4′‐oxybis(5‐methoxy‐2‐methyl‐3,4‐dihydro‐2H‐1‐benzopyran), and a new aliphatic compound, (3E,5Z,8S,10E)‐8‐hydroxytrideca‐3,5,10,12‐tetraen‐2‐one, together with three known benzopyran derivatives, were obtained from a mangrove endophytic fungus Penicillium citrinum QJF‐22 collected in Hainan island. Their structures were determined by analysis of spectroscopic data and the relative configuration of (2R,4S)‐5‐methoxy‐2‐methyl‐3,4‐dihydro‐2H‐1‐benzopyran‐4‐ol was also confirmed by single‐crystal X‐ray diffraction. The absolute configurations of four compounds were established by comparison of ECD spectra to calculations. The configuration of (3E,5Z,8S,10E)‐8‐hydroxytrideca‐3,5,10,12‐tetraen‐2‐one was confirmed by comparison of optical value to the similar compound. The configurations of the compounds (2S,4S)‐5‐methoxy‐2‐methyl‐3,4‐dihydro‐2H‐1‐benzopyran‐4‐ol and (2R,4R)‐5‐methoxy‐2‐methyl‐3,4‐dihydro‐2H‐1‐benzopyran‐4‐ol were first determined. (3R,4S)‐3,4,8‐Trihydroxy‐3,4‐dihydronaphthalen‐1(2H)‐one exhibited moderate inhibitory effects on LPS‐induced NO production in RAW264.7 cells with IC₅₀ of 44.7 μM, and without cytotoxicity to RAW264.7 cells within 50 μM.     

Profiling two indole‐2‐carboxamides for allosteric modulation of the CB1 receptor

Allosteric modulation of G‐protein coupled receptors (GPCRs) represents a novel approach for fine‐tuning GPCR functions. The cannabinoid CB1 receptor, a GPCR associated with the CNS, has been implicated in the treatment of drug addiction, pain, and appetite disorders. We report here the synthesis and pharmacological characterization of two indole‐2‐carboxamides:5‐chloro‐3‐ethyl‐1‐methyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1H‐indole‐2‐carboxamide (ICAM‐a) and 5‐chloro‐3‐pentyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1H‐indole‐2‐carboxamide (ICAM‐b). Although both ICAM‐a and ICAM‐b enhanced CP55, 940 binding, ICAM‐b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB1 receptor. Although it displayed negative modulatory effects on G‐protein coupling to CB1, ICAM‐b induced β‐arrestin‐mediated downstream activation of extracellular signal‐regulated kinase (ERK) signaling. These results indicate that this compound represents a novel class of CB1 ligands that produce biased signaling via CB1.     

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

A variety of 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethines and 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin‐induced seizure model. The prepared 1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7‐{(E)‐[(4‐nitrophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, 7‐{(E)‐[(4‐bromo‐2,6‐difluorophenyl)methylidene]amino}‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one and 7‐[(E)‐{[3‐(4‐fluorophenyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7‐[(E)‐{[4‐(dimethylamino)phenyl]methylidene}amino]‐5‐phenyl‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.     

3‐Cl‐AHPC inhibits pro‐HGF maturation by inducing matriptase/HAI‐1 complex formation

Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules.     

Further Thymol Derivatives from Ageratina cylindrica

From the leaves of Ageratina cylindrica, in addition to the described [(2S)‐2‐{4‐formyl‐5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl]methyl benzoate (cylindrinol A, 8 ), seven new thymol derivatives were isolated and named cylindrinols B – H ( 1 – 7 ). The structures of these compounds were established as (2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 1 ), (2‐{4‐formyl‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 2 ), (2‐{4‐[(acetyloxy)methyl]‐2‐[(2‐methylpropanoyl)oxy]phenyl}oxiran‐2‐yl)methyl benzoate ( 3 ), [2‐(2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 4 ), [2‐(5‐hydroxy‐2‐[(2‐methylpropanoyl)oxy]‐4‐{[(2‐methylpropanoyl)oxy]methyl}phenyl)oxiran‐2‐yl]methyl benzoate ( 5 ), 2‐{4‐(hydroxymethyl)‐2‐[(2‐methylpropanoyl)oxy]phenyl}prop‐2‐en‐1‐yl benzoate ( 6 ), and 2‐hydroxy‐2‐[2‐hydroxy‐4‐(hydroxymethyl)‐phenyl]‐3‐[(2‐methylpropanoyl)oxy]propyl benzoate ( 7 ), by spectroscopic means. Compounds 1 showed moderate antiprotozoal activity on both protozoa. Compounds 4 and 5 showed selectivity on Giardia lamblia trophozoites. All isolated compounds were less active than two antiprotozoal drugs, metronidazole and emetine, used as positive controls. Compound 5 exhibited a high inhibitory effect on hyperpropulsive movement of the small intestine in rats; its effect was best than loperamide, antidiarrheal drug used as a positive control.     

Synthesis of Novel Aryloxyethylamine Derivatives and Evaluation of Their in Vitro and in Vivo Neuroprotective Activities

A series of aryloxyethylamine derivatives were designed, synthesized and evaluated for their biological activity. Their structures were confirmed by ¹H‐NMR, ¹³C‐NMR, FT‐IR and HR‐ESI‐MS. The preliminary screening of neuroprotection of compounds in vitro was detected by MTT, and the anti‐ischemic activity in vivo was tested using bilateral common carotid artery occlusion in mice. Most of these compounds showed potential neuroprotective effects against the glutamate‐induced cell death in differentiated rat pheochromocytoma cells (PC12 cells), especially for (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone, (4‐bromophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, (4‐chlorophenyl)(1‐{2‐[(naphthalen‐2‐yl)oxy]ethyl}piperidin‐4‐yl)methanone, (4‐chlorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone and {1‐[2‐(4‐bromophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone, which exhibited potent protection of PC12 cells at three doses (0.1, 1.0, 10 μM). Compounds (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, (4‐fluorophenyl){1‐[2‐(naphthalen‐2‐yloxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed the significant prolongation of the survival time of mice subjected to acute cerebral ischemia and decreased the mortality rate at all five doses tested (200, 100, 50, 25, 12.5 mg/kg) and had significant neuroprotective activity. In addition, (4‐fluorophenyl){1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}methanone, {1‐[2‐(4‐methoxyphenoxy)ethyl]piperidin‐4‐yl}(4‐methoxyphenyl)methanone and {1‐[2‐(4‐chlorophenoxy)ethyl]piperidin‐4‐yl}(4‐chlorophenyl)methanone possessed outstanding neuroprotection in vitro and in vivo. These compounds can be used as a promising neuroprotective agents for future development of new anti‐ischemic stroke agents. Basic structure–activity relationships are also presented.     

Germanium‐ and Silicon‐Substituted Donor–Acceptor Type Copolymers: Effect of the Bridging Heteroatom on Molecular Packing and Photovoltaic Device Performance

The effects of heteroatom substitution from a silicon atom to a germanium atom in donor‐acceptor type low band gap copolymers, poly[(4,4′‐bis(2‐ethylhexyl)dithieno[3,2‐b:2′,3′‐d]silole)‐2,6‐diyl‐alt‐(2,1,3‐benzothiadiazole)‐4,7‐diyl] (PSiBTBT) and poly[(4,4′‐bis(2‐ethylhexyl)dithieno[3,2‐b:2′,3′‐d]germole)‐2,6‐diyl‐alt‐(2,1,3‐benzothiadiazole)‐4,7‐diyl] (PGeBTBT), are studied. The optoelectronic and charge transport properties of these polymers are investigated with a particular focus on their use for organic photovoltaic (OPV) devices in blends with phenyl‐C₇₀‐butyric acid methyl ester (PC₇₀BM). It is found that the longer C‐Ge bond length, in comparison to C‐Si, modifies the molecular conformation and leads to a more planar chain conformation in PGeBTBT than PSiBTBT. This increase in molecular planarity leads to enhanced crystallinity and an increased preference for a face‐on backbone orientation, thus leading to higher charge carrier mobility in the diode configuration. These results provide important insight into the impact of the heavy atom substitution on the molecular packing and device performance of polymers based on the poly[2,6‐(4,4‐bis‐(2‐ethylhexyl)‐4H‐cyclopenta[2,1‐b;3,4‐b]‐dithiophene)‐alt‐4,7‐(2,1,3‐benzothiadiazole) (PCPDTBT) backbone.     

Homo‐C‐nucleoside analogs IV. Synthesis of 4‐(2,5‐anhydro‐D‐altro‐pentitol‐1‐yl)‐2‐phenyl‐2H‐1,2,3‐triazole homo‐C‐nucleoside. CD assignment of the absolute configuration of the carbon bridge

Dehydrative cyclization of 4‐(D‐altro ‐pentitol‐1‐yl)2‐phenyl‐2H ‐1,2,3‐triazole in basic medium with one moler equivalent of p‐toluene sulfonyl chloride in pyridine solution gave the homo‐C‐ nucleoside 4‐(2,5‐anhydro‐D‐altro ‐1‐yl)‐2‐phenyl‐2H ‐1,2,3‐triazole. The structure and anomeric configuration was determined by acylation, nuclear magnetic resonance (NMR), and mass spectroscopy. The stereochemistry at the carbon bridge of homo‐C‐ nucleoside 2‐phenyl‐2H ‐1,2,3‐triazoles was determined by circular dichroism (CD) spectroscopy.     

Triterpenoids from the Roots of Craibiodendron henryi W. W. Smith

A new triterpenoid, 11a.O.trans-p-coumaroyltaraxerol （1）, along with 11 known triterpenoids, taraxerone （2）, taraxerol （3）, 2α,3β,23,24-tetrahydroxyolean-12-en-28-oic acid （4）, oleanolic acid （5）, β-amyrin （6）, 3β,23-dihydroxylursan-12-en- 28-oic acid （7）, 2α,3β-dihydroxyursan-12-en-28-oic acid （8）, 2α,3β,23-trihydroxyursan-12-en-28-oic acid （9）, 2α,3β,24- trihydroxyursan-12-en-28-oic acid （10）, u rsolic acid （11）, and 3-O-acetylursolic acid （12）, was isolated from Craibiodendron henryi W. W. Smith （Ericaceae）. The structures of these compounds were elucidated on the basis of spectral evidence. Antioxidant activity and vasodilator effect of compound 1 were assessed.     

Insight into antioxidant properties of milk‐derived bioactive peptides in vitro and in a cellular model

Milk is a nutritionally important source of bioactive peptides with anti‐inflammatory, immunomodulatory, anticancer, and antioxidant properties. These compounds can be useful as ingredients of functional food. For this reason, in the last decades, bioactive peptides attracted the interest of researchers and food companies. In this work, the results obtained with six milk‐derived bioactive peptides (Y‐4‐R, V‐6‐R, V‐7‐K, A‐10‐F, R‐10‐M, and H‐9‐M) synthesized and studied for their antioxidant properties in vitro and in a cellular model, are reported. These molecules correspond to peptide fragments derived from parent compounds able to cross the apical membrane of Caco‐2 cell layer and released in the basolateral compartment. In vitro, antioxidant tests such as 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulphonic acid) (ABTS) and crocin bleaching showed antioxidant activity mainly for peptides Y‐4‐R and V‐6‐R, respectively. In Caco‐2 cells, peptides V‐6‐R, H‐9‐R, Y‐4‐R, and particularly R‐10‐M and V‐7‐K are able to prevent the decrease of viability due to oxidative stress. The latter peptide is also the most effective in protecting cells from lipid peroxidation. In conclusion, the reported hydrolyzed peptides are shown to exert the antioxidant properties both in vitro and in a cellular model.     

Design and Synthesis of Novel Arylisoxazole‐Chromenone Carboxamides: Investigation of Biological Activities Associated with Alzheimer's Disease

A novel series of hybrid arylisoxazole‐chromenone carboxamides were designed, synthesized, and evaluated for their cholinesterase (ChE) inhibitory activity based on the modified Ellman's method. Among synthesized compounds, 5‐(3‐nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide depicted the most acetylcholinesterase (AChE) inhibitory activity (IC₅₀=1.23 μm ) and 5‐(3‐chlorophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide was found to be the most potent butyrylcholinesterase (BChE) inhibitor (IC₅₀=9.71 μm ). 5‐(3‐Nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide was further investigated for its BACE1 inhibitory activity as well as neuroprotectivity and metal chelating ability as important factors involved in onset and progress of Alzheimer's disease. It could inhibit BACE1 by 48.46 % at 50 μm . It also showed 6.4 % protection at 25 μm and satisfactory chelating ability toward Zn²⁺, Fe²⁺, and Cu²⁺ ions. Docking studies of 5‐(3‐nitrophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide and 5‐(3‐chlorophenyl)‐N‐{4‐[(2‐oxo‐2H‐1‐benzopyran‐7‐yl)oxy]phenyl}‐1,2‐oxazole‐3‐carboxamide confirmed desired interactions with those amino acid residues of the AChE and BChE, respectively.     

Inhibition of NO Production by Grindelia argentina and Isolation of Three New Cytotoxic Saponins

A bioassay‐guided phytochemical analysis of the ethanolic extract of Grindelia argentina Deble & Oliveira ‐Deble (Asteraceae) allowed the isolation of a known flavone, hispidulin, and three new oleanane‐type saponins, 3‐O‐β‐D ‐xylopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐2β,3β,16α,23‐tetrahydroxyolean‐12‐en‐28‐oic acid 28‐O‐β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐apiofuranosyl‐(1→3)‐β‐D ‐xylopyranosyl‐(1→3)‐α‐L ‐rhamnopyranosyl‐(1→2)‐α‐L ‐arabinopyranosyl ester ( 2 ), 3‐O‐β‐D ‐glucopyranosyl‐2β,3β,23‐trihydroxyolean‐12‐en‐28‐oic acid 28‐O‐β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐apiofuranosyl‐(1→3)‐β‐D ‐xylopyranosyl‐(1→3)‐α‐L ‐rhamnopyranosyl‐(1→2)‐α‐L ‐arabinopyranosyl ester, ( 3 ) and 3‐O‐β‐D ‐xylopyranosyl‐(1→3)‐β‐D ‐glucopyranosyl‐2β,3β,23‐trihydroxyolean‐12‐en‐28‐oic acid 28‐O‐β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐apiofuranosyl‐(1→3)‐β‐D ‐xylopyranosyl‐(1→3)‐α‐L ‐rhamnopyranosyl‐(1→2)‐α‐L ‐arabinopyranosyl ester ( 4 ), named grindeliosides A–C, respectively. Their structures were determined by extensive 1D‐ and 2D‐NMR experiments along with mass spectrometry and chemical evidence. The isolated compounds were evaluated for their inhibitory activities against LPS/IFN‐γ‐induced NO production in RAW 264.7 macrophages and for their cytotoxic activities against the human leukemic cell line CCRF‐CEM and MRC‐5 lung fibroblasts. Hispidulin markedly reduced LPS/IFN‐γ‐induced NO production (IC₅₀ 51.4 μM ), while grindeliosides A–C were found to be cytotoxic, with grindelioside C being the most active against both CCRF‐CEM (IC₅₀ 4.2±0.1 μM ) and MRC‐5 (IC₅₀ 4.5±0.1 μM ) cell lines.     

Two New Pyrrolosesquiterpenes Produced by a Streptomyces Species

Two new pyrrolosesquiterpenes, 1 and 2 , were isolated from cultures of the soil actinomycete Streptomyces sp. Hd7–21. The structures of these compounds were established as (2Z,4E,9E)‐6,7,11‐trihydroxy‐3,7,11‐trimethyl‐1‐(1H‐pyrrol‐2‐yl)dodeca‐2,4,9‐trien‐1‐one ( 1 ) and (2Z,4E)‐5‐{3‐[(2E)‐4‐hydroxy‐4‐methylpent‐2‐en‐1‐yl]‐3‐methyloxiran‐2‐yl}‐3‐methyl‐1‐(1H‐pyrrol‐2‐yl)penta‐2,4‐dien‐1‐one ( 2 ) by extensive spectroscopic analyses including MS, and 1D‐ and 2D‐NMR data. Their cytotoxic activities against a panel of human cancer cell lines were evaluated.     

Four New Chromone Derivatives from Colletotrichum gloeosporioides

Four previously unreported chromones, 5‐hydroxy‐2‐(hydroxymethyl)‐8‐methoxy‐4H‐chromen‐4‐one ( 1 ), (5R,7S)‐5,7‐dihydroxy‐2‐propyl‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 2 ), (5R,7S)‐5,7‐dihydroxy‐2‐methyl‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 3 ), and (5R,7S)‐5,7‐dihydroxy‐2‐[(E)‐prop‐1‐en‐1‐yl]‐5,6,7,8‐tetrahydro‐4H‐chromen‐4‐one ( 4 ), as well as one known analogue 5‐hydroxy‐2‐methyl‐4H‐chromen‐4‐one ( 5 ) were isolated from the fermentation broth of the endophytic fungus Colletotrichum gloeosporioides derived from the mangrove Ceriops tagal. Their structures were elucidated based on extensive spectroscopic analyses. The absolute configurations of 2 – 4 were determined by comparison the experimental and calculated electronic circular dichroism (ECD) spectra. Compound 2 showed cytotoxic activity against A549 cell line with the IC₅₀ value of 0.094 mm .     

Long noncoding RNA HOXA‐AS2 mediates microRNA‐106b‐5p to repress sepsis‐engendered acute kidney injury

HOXA cluster antisense RNA 2 (HOXA‐AS2) is a long noncoding RNA associated with the development of numerous cancers. But, whether HOXA‐AS2 exhibits a certain function in sepsis‐engendered acute kidney injury (AKI) remains uninvestigated. We strived to unveil the role of HOXA‐AS2 in sepsis‐engendered AKI. The expression of HOXA‐AS2 in sepsis patients, animal models and lipopolysaccharide (LPS)‐impaired HK‐2 cells was primarily assessed via a real‐time quantitative polymerase chain reaction. The effects of HOXA‐AS2 on cell survival of HK‐2 cells under LPS irritation were evaluated after overexpression of HOXA‐AS2. The correlation between HOXA‐AS2 and microRNA (miR)‐106b‐5p was forecasted via bioinformatics software and verified by using a luciferase report system. Subsequently, the functions of miR‐106b‐5p in LPS‐damaged HK‐2 cells were reassessed. Western blot was used for the determination of Wnt/β‐catenin and nuclear factor‐κB (NF‐κB) pathways. HOXA‐AS2 expression was decreased in sepsis patients, animal operation group and LPS‐irritated HK‐2 cells. Overexpressed HOXA‐AS2 mollified LPS‐triggered impairment in HK‐2 cells. In addition, a negative mediatory relation between HOXA‐AS2 and miR‐106b‐5p was predicated. Synchronously, overexpressed miR‐106b‐5p counteracted the protection of HOXA‐AS2 in LPS‐damaged HK‐2 cells. Ultimately, Wnt/β‐catenin and NF‐κB pathways were hindered by HOXA‐AS2 via targeting miR‐106b‐5p. HOXA‐AS2 exhibited protection in sepsis‐engendered AKI via targeting miR‐106b‐5p and hindering the Wnt/β‐catenin and NF‐κB pathways.     

Stress-related RNase PR-10c is post-translationally modified by glutathione in birch

The PR‐10c (previously termed as Bet v 1‐Sc3) protein of birch belongs to the family of intracellular pathogenesis‐related proteins. The high‐performance liquid chromatography electrospray ionization ion trap mass spectrometry (HPLC‐ESI‐MS) analysis of PR‐10c‐His fusion protein, produced in Escherichia coli, revealed three major peaks and masses. Enzymatic digestions and HPLC‐ESI‐MS and matrix assisted laser desorption/ionization – time of flight mass spectrometry (MALDI‐TOF‐MS) analyses of each fraction indicated that PR‐10c‐His protein is post‐translationally modified by carbamylation and S‐glutathiolation. Carbamylation was localized into the N‐terminal end of PR‐10c‐His and does not represent a biologically significant modification. The possible nuclease activity of PR‐10c was analysed with S‐glutathiolated and reduced fractions of PR‐10c‐His fusion protein. Both forms of PR‐10c‐His as well as the dimeric form of the protein possess RNase activity which is capable of digesting different RNA substrates. None of the fractions showed activity against single‐ or double‐stranded DNA. The MALDI‐TOF‐MS analysis of PR‐10c polypeptide extracted from zinc‐exposed birch roots showed that the protein is post‐translationally modified by glutathione (γ‐Glu‐Cys‐Gly) also in vivo. The S‐glutathiolated cysteine residue of PR‐10c is not conserved among Bet v 1 homologous proteins and is also unique in the PR‐10 family. As far as we know this is the first observation of S‐glutathiolation in plants, or any post‐translational modification in the PR‐10 family of proteins.