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1.
Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)‐carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late‐stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one‐pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti‐fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.  相似文献   

2.
Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)‐carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late‐stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one‐pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti‐fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.  相似文献   

3.
Two novel coordination polymers, [Ag(L1)(NO3)]n 1 and [Ag(L2)2(ClO4)]n 2 [L1 = 1‐(1‐benzotriazole‐yl‐)triazole, L2 = 1‐(4‐chloro‐pyridazine‐yl‐)triazole] have been synthesized and characterized. Single‐crystal X‐ray analyses show that the Ag(I) atom is in a four‐coordinated distorted tetrahedron environment, which are linked by the coordinated nitrate group and L1 into a two‐dimensional network in complex 1 . While in the complex 2 , the Ag(I) is also in a distorted tetrahedron environment consisting of four N atoms to present a one‐dimensional infinite chain, the intermolecular π? π stacking action extends further the repeated units into three‐dimensional topological framework. The biological activities of the title compounds have been studied. The results indicate that two ligands exhibit excellent radical‐scavenging activities and certain fungicidal activities, and both Ag(I) complexes only have good antibacterial activities. Furthermore, the studies on luminescent properties of the complexes in the solid state indicate that the Ag(I) complexes exhibit weaker fluoresce intensity than that of ligands at room temperature. Copyright © 2008 John Wiley & Sons, Ltd.  相似文献   

4.
[Fe]‐hydrogenase (Hmd) catalyzes the reversible hydrogenation of methenyl‐tetrahydromethanopterin (methenyl‐H4MPT+) with H2. H4MPT is a C1‐carrier of methanogenic archaea. One bacterial genus, Desulfurobacterium, contains putative genes for the Hmd paralog, termed HmdII, and the HcgA–G proteins. The latter are required for the biosynthesis of the prosthetic group of Hmd, the iron–guanylylpyridinol (FeGP) cofactor. This finding is intriguing because Hmd and HmdII strictly use H4MPT derivatives that are absent in most bacteria. We identified the presence of the FeGP cofactor in D. thermolithotrophum. The bacterial HmdII reconstituted with the FeGP cofactor catalyzed the hydrogenation of derivatives of tetrahydrofolate, the bacterial C1‐carrier, albeit with low enzymatic activities. The crystal structures show how Hmd recognizes tetrahydrofolate derivatives. These findings have an impact on future biotechnology by identifying a bacterial Hmd paralog.  相似文献   

5.
In this study, a series of secondary‐ and tertiary‐amino‐substituted diaryl diselenides were synthesized and studied for their glutathione peroxidase (GPx) like antioxidant activities with H2O2, cumene hydroperoxide, or tBuOOH as substrates and with PhSH or glutathione (GSH) as thiol cosubstrates. This study reveals that replacement of the tert‐amino groups in benzylamine‐based diselenides by sec‐amino moieties drastically enhances the catalytic activities in both the aromatic thiol (PhSH) and GSH assay systems. Particularly, the N‐propyl‐ and N‐isopropylamino‐substituted diselenides are 8–18 times more active than the corresponding N,N‐dipropyl‐ and N,N‐diisopropylamine‐based compounds in all three peroxide systems when GSH is used as the thiol cosubstrate. Although the catalytic mechanism of sec‐amino‐substituted diselenides is similar to that of the tert‐amine‐based compounds, differences in the stability and reactivity of some of the key intermediates account for the differences in the GPx‐like activities. It is observed that the sec‐amino groups are better than the tert‐amino moieties for generating the catalytically active selenols. This is due to the absence of any significant thiol‐exchange reactions in the selenenyl sulfides derived from sec‐amine‐based diselenides. Furthermore, the seleninic acids (RSeO2H) derived from the sec‐amine‐based compounds are more stable toward further reactions with peroxides than their tert‐amine‐based analogues.  相似文献   

6.
Lantibiotics are a type of ribosomally synthesized and post‐translationally modified peptides (termed lanthipeptides) with often potent antimicrobial activity. Herein, we report the discovery of a new lantibiotic, lexapeptide, using the library expression analysis system (LEXAS) approach. Lexapeptide has rare structural modifications, including N‐terminal (N,N)‐dimethyl phenylalanine, C‐terminal (2‐aminovinyl)‐3‐methyl‐cysteine, and d ‐Ala. The characteristic lanthionine moiety in lexapeptide is formed by three proteins (LxmK, LxmX, and LxmY), which are distinct from enzymes known to be involved in lanthipeptide biosynthesis. Furthermore, a novel F420H2‐dependent reductase (LxmJ) from the lexapeptide biosynthetic gene cluster (BGC) is identified to catalyze the reduction of dehydroalanine to install d ‐Ala. Our findings suggest that lexapeptide is the founding member of a new class of lanthipeptides that we designate as class V. We also identified further class V lanthipeptide BGCs in actinomycetes and cyanobacteria genomes, implying that other class V lantibiotics await discovery.  相似文献   

7.
The theoretical studies on three‐dimensional quantitative structure activity relationship (3D‐QSAR) and action mechanism of a series of 2‐indolinone derivatives as tubulin inhibitors against human breast cancer cell line MDA‐MB‐231 have been carried out. The established 3D‐QSAR model from the comparative molecular field analysis (CoMFA) shows not only significant statistical quality but also predictive ability, with high correlation coefficient (R2 = 0.986) and cross‐validation coefficient (q2 = 0.683). In particular, the appropriate binding orientations and conformations of these 2‐indolinone derivatives interacting with tubulin are located by docking study, and it is very interesting to find that the plot of the energy scores of these compounds in DOCK versus the corresponding experimental pIC50 values exhibits a considerable linear correlation. Therefore, the inhibition mechanism that 2‐indolinone derivatives were regarded as tubulin inhibitors can be theoretically confirmed. Based on such an inhibition mechanism along with 3D‐QSAR results, some important factors improving the activities of these compounds were discussed in detail. These factors can be summarized as follows: the H atom adopted as substituent R1, the substituent R2 with higher electropositivity and smaller bulk, the substituents R4–R6 (on the phenyl ring) with higher electropositivity and larger bulk, and so on. These results can offer useful theoretical references for understanding the action mechanism, designing more potent inhibitors, and predicting their activities prior to synthesis. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2009  相似文献   

8.
Here we report the direct chemical synthesis of coenzyme B12 (AdoCbl) from Coβ ‐5′‐deoxyadenosylcobyric acid (AdoCby) and the preparation of the latter from crystalline CN ,H2O‐cobyric acid (CN ,H2OC by). AdoCby is a suggested common key intermediate in the biosynthesis of AdoCbl and of other cobamides in microorganisms. AdoCby was thoroughly characterized by spectroscopic means, including homo‐nuclear and hetero‐nuclear NMR , as such data are not available in published work. AdoCbl was prepared from AdoCby in one‐step in over 85% yield, by covalent attachment in aqueous solution of the integral B12‐nucleotide moiety using 1‐ethyl‐3‐(3‐dimethylaminopropyl)‐carbodiimide (EDC ·HC l) and N‐hydroxybenzotriazole (HOB t) as coupling reagents. By the same procedure crystalline vitamin B12 (CNC bl) was also prepared in 92% yield from CN ,H2OC by. Coordination of the B12‐nucleotide base at the Coα ‐face of AdoCby or of CN ,H2OC by was indicated to assist in the efficient covalent coupling at the activated f‐side chain function to furnish the complete corrinoids AdoCbl and CNC bl.  相似文献   

9.
Thiopeptides, arising from complex posttranslational modifications of a genetically encoded precursor peptide, are of great interest due to their structural complexity and important biological activities. All of these antibiotics share a macrocyclic peptidyl core that contains a central, six‐membered nitrogen heterocycle and are classified into five series ae based on the oxidation state of the central nitrogenous ring. Here, we report that the biosynthesis of the central piperidine heterocycle of series a thiopeptides relies on the activity of homologues of an F420H2‐dependent reductase TppX4 by exploiting and characterizing the piperidine‐containing thiopeptin biosynthetic gene (tpp) cluster in Streptomyces tateyamensis. In vitro reconstruction of TppX4 activity demonstrated that the piperidine heterocycle of thiopeptins was transformed from a dehydropiperidine heterocycle, and TppX4 tolerated the changes in the C‐termini and macrocyclic peptidyl core of substrate and also tolerated dehyropiperidine‐containing monocyclic or bicyclic thiopeptides. The identification of TppX4 and its substrate tolerance enriches the biosynthetic toolbox for development of additional thiopeptide analogs for clinical drug screening.  相似文献   

10.
In this paper, we describe the structure‐based design, synthesis, and biological evaluation of cytosine derivatives and analogues that inhibit IspF, an enzyme in the non‐mevalonate pathway of isoprenoid biosynthesis. This pathway is responsible for the biosynthesis of the C5 precursors to isoprenoids, isopentenyl diphosphate (IPP, 1 ) and dimethylallyl diphosphate (DMAPP, 2 ; Scheme 1). The non‐mevalonate pathway is the sole source for 1 and 2 in the protozoan Plasmodium parasites. Since mammals exclusively utilize the alternative mevalonate pathway, the enzymes of the non‐mevalonate pathway have been identified as attractive new drug targets in the fight against malaria. Based on computer modeling (cf. Figs. 2 and 3), new cytosine derivatives and analogues (Fig. 1) were selected as potential drug‐like inhibitors of IspF protein, and synthesized (Schemes 2–5). Determination of the enzyme activity by 13C‐NMR spectroscopy in the presence of the new ligands showed inhibitory activities for some of the prepared cytosine and pyridine‐2,5‐diamine derivatives in the upper micromolar range (IC50 values; Table). The data suggest that it is possible to inhibit IspF protein without binding to the polar diphosphate binding site and the side chain of Asp56′, which interacts with the ribose moiety of the substrate and substrate analogues. Furthermore, a new spacious sub‐pocket was discovered which accommodates aromatic spacers between cytosine derivatives or analogues (binding to ‘Pocket III’) and rings that occupy the flexible hydrophobic region of ‘Pocket II’. The proposed binding mode remains to be further validated by X‐ray crystallography.  相似文献   

11.
In the chiral polymeric title compound, poly[aqua(4,4′‐bipyridine)[μ3S‐carboxylatomethyl‐N‐(p‐tosyl)‐l ‐cysteinato]manganese(II)], [Mn(C12H13NO6S2)(C10H8N2)(H2O)]n, the MnII ion is coordinated in a distorted octahedral geometry by one water molecule, three carboxylate O atoms from three S‐carboxyatomethyl‐N‐(p‐tosyl)‐l ‐cysteinate (Ts‐cmc) ligands and two N atoms from two 4,4′‐bipyridine molecules. Each Ts‐cmc ligand behaves as a chiral μ3‐linker connecting three MnII ions. The two‐dimensional frameworks thus formed are further connected by 4,4′‐bipyridine ligands into a three‐dimensional homochiral metal–organic framework. This is a rare case of a homochiral metal–organic framework with a flexible chiral ligand as linker, and this result demonstrates the important role of noncovalent interactions in stabilizing such assemblies.  相似文献   

12.
AgI‐containing coordination complexes have attracted attention because of their photoluminescence properties and antimicrobial activities and, in principle, these properties depend on the nature of the structural topologies. A novel two‐dimensional silver(I) complex with the anti‐inflammatory diclofenac molecule, namely bis{μ‐2‐[2‐(2,6‐dichloroanilino)phenyl]acetato‐κ3O,O′:O}bis(μ‐2,5‐dimethylpyrazine‐κ2N:N′)silver(I), [Ag2(C14H10Cl2NO2)2(C6H8N2)]n, (I), has been synthesized and characterized by single‐crystal X‐ray diffraction, revealing that the AgI ions are chelated by the carboxylate groups of the anionic 2‐[2‐(2,6‐dichloroanilino)phenyl]acetate (dicl) ligand in a μ3‐η12 coordination mode. Each dicl ligand links three AgI atoms to generate a one‐dimensional infinite chain. Adjacent chains are connected through 2,5‐dimethylpyrazine (dmpyz) ligands to form a two‐dimensional layer structure parallel to the crystallographic bc plane. The layers are further connected by C—H…π interactions to generate a three‐dimensional supramolecular structure. Additionally, the most striking feature is that the structure contains an intramolecular C—H …Ag anagostic interaction. Furthermore, the title complex has been tested for its in vitro antibacterial activity and is determined to be highly effective on the studied microorganisms.  相似文献   

13.
The fungus Xylaria arbuscula was isolated as an endophyte from Cupressus lusitanica and has shown to be a prominent producer of cytochalasins, mainly cytochalasins C, D and Q. Cytochalasins comprise an important class of fungal secondary metabolites that have aroused attention due to their uncommon molecular structures and pronounced biological activities. Due to the few published studies on the ESI‐MS/MS fragmentation of this important class of secondary metabolites, in the first part of our work, we studied the cytochalasin D fragmentation pathways by using an ESI‐Q‐ToF mass spectrometer coupled with liquid chromatography. We verified that the main fragmentation routes were generated by hydrogen and McLafferty rearrangements which provided more ions than just the ones related to the losses of H2O and CO as reported in previous studies. We also confirmed the diagnostic ions at m /z 146 and 120 as direct precursor derived from phenylalanine. The present work also aimed the production of structurally diverse cytochalasins by varying the culture conditions used to grow the fungus X. arbuscula and further insights into the biosynthesis of cytochalasins. HPLC‐MS analysis revealed no significant changes in the metabolic profile of the microorganism with the supplementation of different nitrogen sources but indicated the ability of X. arbuscula to have access to inorganic and organic nitrogen, such as nitrate, ammonium and amino acids as a primary source of nitrogen. The administration of 2‐13C‐glycine showed the direct correlation of this amino acid catabolism and the biosynthesis of cytochalasin D by X. arbuscula , due to the incorporation of three labeled carbons in cytochalasin chemical structure. Copyright © 2017 John Wiley & Sons, Ltd.  相似文献   

14.
In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt‐containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer‐assisted structure prediction algorithm, and X‐ray crystallography. The compounds, named armeniaspirol A–C ( 2 – 4 ), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐13C] acetate, [1,2‐13C2] acetate, and [U‐13C] proline suggest a biosynthesis through a rare two‐chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against Gram‐positive pathogens such as methicillin‐resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure.  相似文献   

15.
1,3‐Enyne structural motifs are versatile building blocks in organic synthesis and occur widely in various natural products with many of them being highly active as cytotoxic macrolides and antitumour antibiotics. This article presents the crystal structure of three 1,1,4‐triphenyl‐substituted 1,3‐enynes, viz. 4‐(2‐methylphenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C23H18 ( 1 ), 4‐(2‐methoxyphenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C23H18O ( 2 ), and 4‐(4‐nitrophenyl)‐1,1‐diphenylbut‐1‐en‐3‐yne, C22H15NO2 ( 3 ). The benzene ring at position 4 of the but‐1‐en‐3‐yne group bears a weakly activating methyl group in compound 1 , a moderately activating methoxy group in 2 and a strongly deactivating nitro group in 3 . The crystal structures of 1 and 3 both have monoclinic symmetry, while that of 2 is orthorhombic, and all of them have one molecule in the asymmetric unit. All three compounds were investigated for their antibacterial and antifungal activities. Interestingly, enyne 2 is the only compound tested that inhibited the growth of Aspergillus niger.  相似文献   

16.
The radical S‐adenosylmethionine (SAM) aminomutases represent an important pathway for the biosynthesis of β‐amino acids. In this study, we report biochemical characterization of BlsG involved in blasticidin S biosynthesis as a radical SAM arginine 2,3‐aminomutase. We showed that BlsG acts on both L‐arginine and L‐lysine with comparable catalytic efficiencies. Similar dual substrate specificity was also observed for the lysine 2,3‐aminomutase from Escherichia coli (LAMEC). The catalytic efficiency of LAMEC is similar to that of BlsG, but is significantly lower than that of the enzyme from Clostridium subterminale (LAMCS), which acts only on L‐lysine rather than on L‐arginine. Moreover, we showed that enzymes can be grouped into two major phylogenetic clades, each corresponding to a certain C3 stereochemistry of the β‐amino acid product. Our study expands the radical SAM aminomutase members and provides insights into enzyme evolution, supporting a trade‐off between substrate promiscuity and catalytic efficiency.  相似文献   

17.
Among different metallic nanoparticles, sliver nanoparticles (Ag NPs) are one of the most essential and fascinating nanomaterials. Importantly, among the metal based nanoparticles, Ag NPs play a key role in various fields such as biomedicine, biosensors, catalysis, pharmaceuticals, nanoscience and nanotechnology, particularly in nanomedicine. A main concern about the chemical synthesis of Ag NPs is the production of hazardous chemicals and toxic wastes. To overcome this problem, many research studies have been carried out on the green synthesis of Ag NPs using green sources such as plant extracts, microorganisms and some biopolymers without formation of hazardous wastes. Among green sources, plants could be remarkably valuable to exploring the biosynthesis of Ag NPs. In this review, the green synthesis of Ag‐based nanocatalysts such as Ag NPs, AgPd NPs, Au?Ag NPs, Ag/AgPd NPs, Ag/Cu NPs, Ag@AgCl NPs, Au?Ag@AgCl nanocomposite, Ag?Cr‐AC nanocomposite and Ag NPs immobilized on various supports such as Natrolite zeolite, bone, ZnO, seashell, hazelnut shell, almond shell, SnO2, perlite, ZrO2, TiO2, α‐Al2O3, CeO2, reduced graphene oxide (rGO), h‐Fe2O3@SiO2, and Fe3O4 using numerous plant extracts as reducing and stabilizing agents in the absence of hazardous surfactant and capping agents has been focused. This work describes the state of the art and future challenges in the biosynthesis of Ag‐based nanocatalysts. The fact about the application of living plants in metal nanoparticle (MNPs) industry is that it is a more economical and efficient biosynthesis biosynthetic procedure. In addition, the catalytic activities of the synthesized, Ag‐based recyclable nanocatalysts using various plant extracts in several chemical reactions such as oxidation, reduction, coupling, cycloaddition, cyanation, epoxidation, hydration, degradation and hydrogenation reactions have bben extensively discussed.  相似文献   

18.
A series of triorganotin chrysanthemumates (2,2‐dimethyl‐3‐(2‐methyl‐1‐propenyl)cyclopropanecarboxylates) (R3SnO2CC9H15) where R = methyl, ethyl, n‐butyl and phenyl was synthesized. The solid state structures were deduced using infrared (IR) and Mössbauer spectroscopies. The spectroscopic results indicated that all the compounds were found to be five‐coordinated in the solid state. Based on the NMR results, all the compounds are tetrahedral in solution. Larvicidal activities of the compounds were evaluated against the second instar stage of Aedes aegypti, Anopheles stephensi and Culex pipiens quinquefasciatus mosquitoes. The toxicity results indicated that these compounds of triorganotins were effective larvicides against all three species of larvae. Copyright © 2011 John Wiley & Sons, Ltd.  相似文献   

19.
HMG‐CoA reductase inhibitors were widely used as lipid‐lowing agents through effectively blocking the rate‐limiting step of cholesterol biosynthesis. 8 analogs of Rosuvastatin were firstly prepared with different distance and functional group between the O5‐hydroxyl group and terminal COOH group in the hydrophilic side‐chain. In primary and secondary screening of the inhibitory activities against human HMG‐CoA reductase, gem‐difluoromethylenated derivatives exhibited more than 50% inhibition rate. Then 4 compounds with gem‐difluoro group were further synthesized and evaluated in vitro, three compounds among them exhibited low single digital nmol/L IC50 values against HMG‐CoA reductase. Molecular docking also well explained the observed special contribution of the gem‐difluoro group.  相似文献   

20.
In this study, three novel complexes comprising trivalent Cr (III), Fe (III) and Ru (III) with imine ligand derived from 2‐amino‐3‐hydroxypyridine and o‐vanillin (H2L) have been synthesized and characterized via wide range of spectroscopic and analytical tools such as 1H NMR and 13C NMR, infrared (IR) and UV–Vis spectrophotometry, conductivity and magnetic measurements. The obtained results along with DFT data confirmed a 1:1 (metal: ligand) stoichiometry with non‐planner geometries for the three complexes. The binding action and the docking study of the prepared metal‐complexes to calf thymus DNA was also studied by absorption spectra and viscosity technique, which revealed that the three complexes interact strongly with DNA through intercalative binding mode. Significantly, these metal‐imine complexes showed strong and efficient anti‐inflammatory and antimicrobial activities against various gram‐positive (Microccus luteus), gram‐negative (Escherichia coli and Serratia marcescence) bacteria, and three strains of fungus. Moreover, all complexes exhibited more potent cytotoxicity effect on the outgrowth of different types of carcinoma cells, including human colon (HCT‐116 cell line), breast (MCF‐7 cell line), and hepatic cellular (HepG‐2), than the clinically‐proven Vinblastine standard.  相似文献   

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