Highly Stable,Amide‐Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus

Blocking quorum sensing (QS) pathways has attracted considerable interest as an approach to suppress virulence in bacterial pathogens. Toward this goal, we recently developed analogues of a native autoinducing peptide (AIP‐III) signal that can inhibit AgrC‐type QS receptors and attenuate virulence phenotypes in Staphylococcus aureus. Application of these compounds is limited, however, as they contain hydrolytically unstable thioester linkages and have only low aqueous solubilities. Herein, we report amide‐linked AIP analogues with greatly enhanced hydrolytic stabilities and solubilities relative to our prior analogues, whilst maintaining strong potencies as AgrC receptor inhibitors in S. aureus. These compounds represent powerful tools for the study of QS.     

Highly Stable,Amide‐Bridged Autoinducing Peptide Analogues that Strongly Inhibit the AgrC Quorum Sensing Receptor in Staphylococcus aureus

Blocking quorum sensing (QS) pathways has attracted considerable interest as an approach to suppress virulence in bacterial pathogens. Toward this goal, we recently developed analogues of a native autoinducing peptide (AIP‐III) signal that can inhibit AgrC‐type QS receptors and attenuate virulence phenotypes in Staphylococcus aureus. Application of these compounds is limited, however, as they contain hydrolytically unstable thioester linkages and have only low aqueous solubilities. Herein, we report amide‐linked AIP analogues with greatly enhanced hydrolytic stabilities and solubilities relative to our prior analogues, whilst maintaining strong potencies as AgrC receptor inhibitors in S. aureus. These compounds represent powerful tools for the study of QS.     

新型甾体血管新生抑制剂Cortistatin的结构、生物活性与合成

由于肿瘤的生长与转移高度依赖于血管新生,因此发现和发明新型血管新生抑制剂对肿瘤疾病治疗有重要意义.以Cortistatin A为代表的Cortistatin类海洋天然产物是一类化学结构新颖、具有显著血管新生抑制作用的甾体化合物.它们具有9-(10,19)-abeo-雄甾烷骨架和氧原子桥连七元B环结构,Cortistatin A对人脐静脉内皮细胞(HUVEC)增殖具有nmol/L级的抑制活性和相对其他细胞系大于3300的选择性指数.综述了Cortistatin及其类似物自发现来两年期间的合成进展情况.     

From Carbohydrates to Complex Organofluorines: Synthesis,Conformation, and Lipophilicity of Multivicinal-Fluorine-Containing Hexitol Analogues

There is growing interest in the preparation of fluorine-containing organic molecules. Multivicinal-fluorine analogues are among the most intriguing and promising compounds, but their physical and biological investigations are held back by challenging syntheses. Herein, we report on the synthesis of a large set of novel polyfluorohexitols. The dominant solution-state conformation of all trifluorohexitols was determined, and the solid-state conformations of some analogues were compared. Finally, the lipophilicity of a large set of polyfluorinated hexopyranose and hexitol analogues was attributed by using a log P determination method based on ¹⁹F NMR spectroscopy.     

Studies on the Synthesis of Di‐ and Trisaccharide Analogues of Moenomycin A. Modifications in Unit E and in the Lipid Part

Routes allowing the synthesis of moenomycin analogues with one modified sugar component and with new lipid parts were developed (see 10c, 12c, 16b , and 20b in Schemes 2–4). It is anticipated that such analogues will be useful for studying the mode of action of the moenomycin‐type transglycosylase inhibitors in detail and for preparing analogues with improved pharmacokinetic properties.     

cis‐Nitenpyram Analogues Containing 1,4‐Dihydropyridine: Synthesis,Insecticidal Activities,and Molecular Docking Studies

A novel series of cis‐nitenpyram analogues ( 2a – 2p ) were designed and prepared by introducing the 1,4‐dihydropyridine, with their cis‐configuration confirmed by X‐ray diffraction. Preliminary bioassays showed that most compounds exhibited good insecticidal activities at 20 mg/L against Aphis medicagini, and analogues 2a and 2d afforded the best activity, and both of them had 100% mortality at 4 mg/L. In addition, molecular docking studies were also performed to model the ligand‐receptor complexes, and the results explained the structure‐activity relationships observed in vitro, which may provide some useful information for future design of new insecticides.     

11‐Hydro­xy‐3,3‐di­methyl‐7,12‐dioxo‐3,4,6,6a,7,12,12a,12b‐octa­hydro­benz­[a]­anthracen‐1‐yl acetate

The Diels–Alder reaction between 5‐hydroxy‐1,4‐naphtho­quinone and 5,5‐di­methyl‐3‐vinyl‐1,2‐cyclo­hexa­dienyl acetate by endo addition gives the title compound, C₂₂H₂₂O₅, in 68% yield. This racemic diastereoisomer has the opposite regiochemistry to ochromycinone analogues produced previously and may allow access to a new type of anticancer‐active saqua­yamycin analogue.     

Highly trans‐Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ‐Deoxygenation and Heck–Matsuda Reaction: Asymmetric Total Synthesis of (−)‐Musellarins A–C and Their Analogues

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans‐2,6‐dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two‐step trans arylation of AR products to access 2,6‐trans‐dihydropyranones. This new trans‐arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier‐type and Tsuji–Trost‐type reactions, was finally enabled by an unprecedented, highly regioselective γ‐deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (?)‐musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three‐to‐six times greater potency than the musellarins as promising new leads.     

On the protonation and deuteration of N,N-disubstituted 2-aminothiophenes, 2-aminothiazoles,and some 3-amino substituted analogues

In contrast to their carbocyclic aniline analogues, N,N-diarylsubtituted 2-aminothiophenes are not protonated at their N-atoms but at the 5-position or, to a smaller extent, at the 3-position of the thiophene nucleus giving rise to cationic species of the Wheland type. However, 5-formyl and 5-acetyl-substituted 2-(N,N-diarylamino)thiophenes are protonated at the corresponding carbonyl moieties. This finding not only enables insight into the mechanism of electrophilic substitution of N,N-disubstituted 2-aminothiophenes but also allows to prepare deurated 2-aminothiophenes by treatment their non-deuterated parent compounds with CF₃COOD.     

Synthesis and antiviral evaluation of some carbonucleoside analogues

1,2‐O‐Isopropylidene‐α‐L‐threofuranosyl heterocyclic derivatives were synthesized from 1,2‐O‐iso‐propylidene‐α‐D‐xilopentadialdo‐1,4‐furanose and tested for antiviral activity against herpes simplex virus type 1, dengue virus type 2 and Junin virus. For comparative propose, the antiviral activity of some of their pyranosyl analogues were also tested. The furanosyl derivatives showed to be moderate inhibitors of Junin virus and, in general, proved to be more effective than the pyranosyl analogues.     

Synthesis of Bioactive Side‐Chain Analogues of TAN‐2483B

The fungal metabolite TAN‐2483B has a 2,6‐trans‐relationship across the pyran ring of its furo[3,4‐b]pyran‐5‐one core, which has thwarted previous attempts at its synthesis. We have now developed a chiral pool approach to this core and prepared side‐chain analogues of TAN‐2483B. The synthesis relies on ring expansion of a reactive furan ring‐fused dibromocyclopropane and alkynylation of the resulting pyran. The furan ring is constructed by palladium‐catalysed carbonylative lactonisation. Various side‐chains are appended through Wittig‐type chemistry. The prepared analogues showed micromolar activity towards cancer cell lines HL‐60, 1A9 and MCF‐7 and certain human disease‐relevant kinases, including Bruton's tyrosine kinase (Btk).     

Fused 1,2-dithioles. IV. Synthesis and reactions of 1,2-dithiole s-oxides

1,2-Dithiolopyrrolones and their heterologues of type 1 are resonance stabilized systems displaying a high dipole moment. Upon oxidation with organic peracids compounds 2 , 5 , 15a, 16a, 20a and 25a gave the corresponding S(2)-oxides and, depending on substituents, in some cases the S(2)- and S(1)-dioxides. The S(2)-monoxides showed a proclivity to disproportionation and were easily reduced to dithioles with symme trical dimethylhydrazine. From S(2)-oxides and several primary amines bicyclic isothiazole-S-oxides were obtained (S/N-exchange reaction). From the N-unsubstituted isothiazole S-oxide 10e the N-hydroxyisothiazole 9d was synthesized by an aza-Pummerer-type rearrangement. The assumption is made that S(2)-oxides may be biologically important as active metabolites of pyrrothines and analogues of type 1 in their action as antibacterials and antimycobacterials.     

Facile Synthesis of Aryl‐Pyridyl,Pyridazinyl, Pyrazinyl,and Triazinyl Acetonitriles

Dihalo pyridine, pyrazine, and pyridazine analogues were converted to the corresponding monohalo acetonitrile analogues through nucleophilic displacement of the halogen with the anion of tert‐butyl cyanoacetate. The monohalo acetonitriles reacted under Suzuki or Stille conditions to form the title compounds.     

Herbicidal Activity of Phosphonic,Phosphinic and Phosphinous Acid Analogues of Aromatic Amino Acids

Abstract

Over 40 phosphonic, phosphinic and phosphinous acid analogues of phenylglycine and phenylalanine were synthesized and screened for their herbicidal activity on Lepidium sativum (crest) and Cucumis sativus (cucumber). The most active appeared to be 2-amino-1-hydroxy-3-phenylpropylphosphonic acid which was equipotent with popular herbicide glyphosate. Also aminobenzylphosphonic acids, analogues of phenylglycine, exhibited notable herbicidal activity and thus represent a group of the most active herbicides found among simple aminophosphonic acids. Other compounds showed moderate herbicidal activity. Preliminary results indicate that analogues of aromatic amino acids display their activity as effectors of biosynthesis of aromatic amino acids.     

Utilisation d'ylides du phosphore en chimie des sucres,X. Synthèse stéréospécifique de l'épimère en C3 du streptose et d'autres sucres ramifiés,dérivés de désoxy-5-pentoses, à groupements gem-hydroxy-formyle ou gem-hydroxy-hydroxyméthyle

The synthesis of branched-chain sugars of the gem-hydroxy-formyl and the gem-hydroxy-hydroxymethyl types is described. A 5-deoxy-1,2-O-isopropylidene-furanos-3-ulose is treated with cyanomethylene-triphenyl-phosphorane, yielding the two geometrical isomers of the corresponding branched-chain unsaturated sugar. Cis-dihydroxylation(KMnO₄) of these cyanomethylenic compounds affords stereoselectively and in high yield the gem-hydroxy-formyl branched chain sugars whose formyl group is on the more hindered face of the furanose ring. The hydroxymethyl analogues of the latter compounds are readily prepared by their borohydride reduction. This method constitutes a new general route to type A branched-chain sugars epimeric at the branching-point with the sugars which would have been obtained by the classical procedure involving Grignard reagents.     

Stachartins A – E,Phenylspirodrimanes from the Tin Mine Tailings‐Associated Fungus Stachybotrys chartarum

Eight phenylspirodrimane‐type analogues, including five new compounds, named stachartins A – E ( 1 , 3 , 6 – 8 ), were isolated from cultures of the tin mine tailings‐associated fungus Stachybotrys chartarum. Their structures were elucidated by spectroscopic methods including extensive 2D‐NMR techniques.     

Design,synthesis, and bioactivity of nortopsentin analogues containing 1,2,4-triazole moieties

Plant diseases are serious and difficult to control. Novel and efficient pesticides are urgently needed. A series of nortopsentin analogues were designed, synthesized, and evaluated for their antiviral activities and fungicidal activities. Compound 3g with higher antiviral activity than nortopsentin D and ribavirin emerged as new antiviral lead compound. Further fungicidal activity tests revealed that nortopsentin analogues displayed broad-spectrum fungicidal activities. Compounds 3a , 3d , and 3f displayed higher antifungal activities against Cercospora arachidicola Hori than commercial fungicides carbendazim and chlorothalonil. Current research has laid a foundation for the application of nortopsentin analogues in plant protection.     

Synthesis,thermal and optical properties of new nanosized polyamides containing N-phenyl- and O-naphthyl-s-triazine rings; part 2

We report the chemistry and properties of two new series of well-defined nano sized spheres aramides-containing N- and O-naphthyl-s-triazines. The polymers were carefully characterized by different techniques including infrared, ultraviolet, fluorescent emission, elemental, thermal analyses and scanning electron microscopy (SEM). The polymers were readily soluble in polar aprotic solvents while insoluble neither in water nor halogenated solvents. Thermal analyses data up to 900°C showed high thermal behavior and the polymers were classified either as “slow burning polymers” or “self-extinguishing polymers” based on their calculated the limiting oxygen index. Interestingly, the naphthyl / phenyl interchange has dramatic improvement on the thermal properties. Obviously, the pyridine / phenylene interchange has no influence on the thermal properties of the addressed polymers. Thermal stability of the aniline-containing polymers proved to be comparable to their naphthylamine analogues. Polymers containing p-phenylene moieties exhibited better thermal results compared to their analogues containing m-phenylene moieties. Benzidine containing polymers and sulfone containing polymers exhibited better thermal stabilities than their analogues containing either ether or methylene flexible linkages. The kinetic data obtained from the nonisothermal decomposition of the prepared polyamides series were also studied. The polymers exhibited emissions ranging from blue to orange wavelength depending on the nature of the signaling unit. The naphthyl / phenyl interchange led to either appreciable red-shifted absorptions in some cases or blue-shifted absorptions in other cases and this behavior may be attributed to the contorted, twisted structural nature of the naphthalene ring. Such attracting properties make these polymers good candidates for applications such as processable high-temperature materials and also as heat-resistant polymeric materials.     

Microsynthesis and electron ionisation mass spectrometric analysis of chemical weapons convention (CWC)-related O,O-dialkyl-N,N-dialkylphosphoramidates

The paper describes microsynthesis and GC/EIMS analysis of O,O-dialkyl-N,N-dialkylphosphoramidates (DADAPs). DADAPs belong to schedule 2B6 category of chemical weapons convention (CWC), as they are important markers of the chemical warfare agent Tabun and its analogues. The study was undertaken to develop a spectral database of DADAPs for verification of CWC. The reported synthetic strategy can be adopted to prepare several analogues of DADAPs simultaneously and rapidly during official proficiency tests, for the unambiguous identification of analytes within a short period. Based on the EIMS data of more than 60 compounds, fragmentation routes are proposed which explain the formation of most of the characteristic fragment ions. Subtle differences in EIMS of isomeric DADAPs are discussed to facilitate their identification.     

Novel open-chain and cyclic conformationally constrained (R)- and (S)-α,α-disubstituted tyrosine analogues

A series of novel open-chain and cyclic conformationally constrained (R)- and (S)-α,α-disubstituted tyrosine analogues 1a–e were synthesized in good yields and high optical purities (Schemes 1 and 2). The absolute configurations of these tyrosine analogues were unambiguously determined based on the X-ray structures of the precursor diastereoisomeric peptides of type 4 and 5 . Four of these structures are described (Figs. 1–4), showing β-turn type-I geometries for dipeptides 4a, 5b , and 4c and an extended conformation for peptide 5c (Table 3). The conversion of the free amino acids 1a–c into suitably protected building blocks 11a–d and 15d,e for peptide synthesis is discussed (Schemes 3 and 4).