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1.
Org Lett ; 22(8): 3176-3179, 2020 04 17.
Article in English | MEDLINE | ID: mdl-32227974

ABSTRACT

We report a relay cross metathesis (ReXM) reaction for the construction of terpenoids in an iterative protocol. The protocol features the cross metathesis of a relay-actuated Δ6,7-functionalized C10-monoterpenoid alcohol with C10-monoterpenoid citral to form a C15-sesquiterpene. Subsequent functional group manipulation allows for the method to be repeated in an iterative fashion. The method is used for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide family of natural products.


Subject(s)
Benzoates/chemistry , Diterpenes/chemical synthesis , Macrolides/chemical synthesis , Terpenes/chemistry , Diterpenes/chemistry , Macrolides/chemistry , Molecular Structure
2.
J Org Chem ; 85(7): 4906-4917, 2020 04 03.
Article in English | MEDLINE | ID: mdl-32191466

ABSTRACT

A retrosynthetic disconnection-reconnection analysis of epoxypolyenes-substrates that can undergo cyclization to podocarpane-type tricycles-reveals relay-actuated Δ6,7-functionalized monoterpenoid alcohols for ruthenium benzylidene catalyzed olefin cross-metathesis with homoprenyl benzenes. Successful implementation of this approach provided several epoxypolyenes as expected (E/Z, ca. 2-3:1). The method is further generalized for the cross-metathesis of pre-existing trisubstituted olefins in other relay-actuated Δ6,7-functionalized monoterpenoid alcohols with various other trisubstituted alkenes to form new trisubstituted olefins. Epoxypolyene cyclization of an enantiomerically pure, but geometrically impure, epoxypolyene substrate provides an enantiomerically pure, trans-fused, podocarpane-type tricycle (from the E-geometrical isomer).

3.
Org Lett ; 21(12): 4703-4708, 2019 06 21.
Article in English | MEDLINE | ID: mdl-31188010

ABSTRACT

Aminobenzaldehydes bearing a pendant 3,5-dinitrophenyl group react thermally with N-substituted α-amino acids to form unprecedented benzoazepine-fused isoindolines. The reaction proceeds via a dearomatization/rearomatization sequence involving an intramolecular (3 + 2)-cycloaddition between the in situ formed azomethine ylide and the dinitroarene. Various glycine derivatives are tolerated as well as branched substrates based on cyclic, α-mono-, and α,α-disubstituted amino acids, giving single diastereomers in many cases. The method is scalable and gives products with a nitro group ready for further manipulation.

4.
Org Lett ; 19(19): 5332-5335, 2017 10 06.
Article in English | MEDLINE | ID: mdl-28933551

ABSTRACT

A series of prenyl-containing malonates are kinetically benchmarked against the standard allyl-containing congeners using a ruthenium benzylidene precatalyst for ring-closing metatheses. The prenyl grouping is found to be a superior acceptor olefin compared to an allyl group in RCM processes with ruthenium alkylidenes derived from terminal alkenes. The prenyl group is also found to be a highly competent acceptor for a ruthenium alkylidene derived from a 1,1-disubstituted olefin in a RCM process.

5.
J Agric Food Chem ; 64(38): 7134-41, 2016 Sep 28.
Article in English | MEDLINE | ID: mdl-27599033

ABSTRACT

Pyrethrum is a natural insecticide extracted from Tanacetum cinerariifolium. Six esters, the pyrethrins, are responsible for the extract's insecticidal activity. The oxidative degradation of pyrethrins through contact with aerial oxygen is a potential cause of pyrethrin losses during pyrethrum manufacture. Described here is the first investigation of the autoxidation chemistry of the six pyrethrin esters isolated from pyrethrum. It was found that pyrethrins I and II, the major pyrethrin esters present in pyrethrum, undergo autoxidation more readily than the minor pyrethrin esters, the jasmolins and cinerins. Chromatographic analysis of pyrethrin I and II autoxidation mixtures showed some correlation with a similar analysis performed on extracts from T. cinerariifolium crop, which had been stored for 12 weeks without added antioxidants. Two pyrethrin II autoxidation products were isolated, characterized, and shown to be present in extracts of stored T. cinerariifolium crop, confirming that autoxidation of pyrethrin esters does occur during crop storage.


Subject(s)
Chrysanthemum cinerariifolium/chemistry , Insecticides/chemistry , Pyrethrins/chemistry , Crops, Agricultural/chemistry , Insecticides/isolation & purification , Oxidation-Reduction , Pyrethrins/isolation & purification
6.
Molecules ; 21(8)2016 Jul 23.
Article in English | MEDLINE | ID: mdl-27455230

ABSTRACT

We provide a comprehensive account of the 1,3-dipolar cycloaddition reactions of azomethine ylides with carbonyl dipolarophiles. Many different azomethine ylides have been studied, including stabilized and non-stabilized ylides. Of the carbonyl dipolarophiles, aldehydes including formaldehyde are the most studied, although there are now examples of cycloadditions with ketones, ketenes and carboxyl systems, in particular isatoic anhydrides and phthalic anhydrides. Intramolecular cycloadditions with esters can also occur under certain circumstances. The oxazolidine cycloadducts undergo a range of reactions triggered by the ring-opening of the oxazolidine ring system.


Subject(s)
Azo Compounds/chemistry , Oxazoles/chemical synthesis , Thiosemicarbazones/chemistry , Cycloaddition Reaction , Molecular Structure , Oxazoles/chemistry , Stereoisomerism
7.
Bioorg Med Chem Lett ; 24(14): 3108-12, 2014 Jul 15.
Article in English | MEDLINE | ID: mdl-24878198

ABSTRACT

Alzheimer's disease is the most common neurodegenerative disease and is one of the main causes of death in developed countries. Consumption of foods rich in polyphenolics is strongly correlated with reduced incidence of Alzheimer's disease. Our study has investigated the biological activity of previously untested polyphenolic compounds in preventing amyloid ß aggregation. The anti-aggregatory potential of these compounds was assessed using the Thioflavin-T assay, transmission electron microscopy, dynamic light scattering and size exclusion chromatography. Two structurally related compounds, luteolin and transilitin were identified as potent inhibitors of Aß fibril formation. Computational docking studies with an X-ray derived oligomeric structure offer a rationale for the inhibitory activity observed and may facilitate development of improved inhibitors of Aß aggregation and toxicity.


Subject(s)
Amyloid beta-Peptides/metabolism , Peptide Fragments/metabolism , Polyphenols/pharmacology , Protein Aggregates/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Polyphenols/chemistry , Polyphenols/isolation & purification , Protein Aggregation, Pathological/prevention & control , Structure-Activity Relationship
8.
Org Biomol Chem ; 12(25): 4432-44, 2014 Jul 07.
Article in English | MEDLINE | ID: mdl-24847981

ABSTRACT

Tercyclic scaffolds, designed to have improved synthetic accessibility and aqueous solubility, were evaluated as structural α-helix mimetics by using an iterative in silico approach. The synthesis of these tercyclic scaffolds was accomplished using a modular synthetic approach by employing functionalised methoxyphenyl units which were readily manipulated to allow the introduction of various nitrogen-based heterocycles. The ability of these scaffolds to mimic the key i, i + 3 and i + 7 residues of a polyalanine α-helix was ratified by in silico studies, X-ray crystallographic and NOESY analysis, and their aqueous solubility was measured by a kinetic turbidimetric method.


Subject(s)
Computer Simulation , Peptides/chemical synthesis , Models, Molecular , Molecular Conformation , Peptides/chemistry , Protein Structure, Secondary , Solubility , Thermodynamics , Water
9.
Org Lett ; 13(3): 486-9, 2011 Feb 04.
Article in English | MEDLINE | ID: mdl-21175141

ABSTRACT

A nonstabilized azomethine ylide reacts with a wide range of substituted isatoic anhydrides to afford novel 1,3-benzodiazepin-5-one derivatives, which are generally isolated in high yield. The transformations involve 1,3-dipolar cycloaddition reactions of the ylide with the anhydrides to give transient, and in a representative case spectroscopically observable, oxazolidine intermediates that undergo ring-opening-decarboxylation-ring-closing reaction cascades to yield the 1,3-benzodiazepin-5-one products.


Subject(s)
Azo Compounds/chemistry , Benzodiazepinones/chemical synthesis , Oxazines/chemistry , Thiosemicarbazones/chemistry , Benzodiazepinones/chemistry , Cyclization , Molecular Structure
10.
Bioorg Med Chem Lett ; 20(2): 649-52, 2010 Jan 15.
Article in English | MEDLINE | ID: mdl-19962303

ABSTRACT

A series of hydrazonotrifluorosulfonanilide derivatives were synthesized and evaluated for in vitro activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. Some compounds with excellent activity against tick were identified.


Subject(s)
Antiparasitic Agents/chemistry , Hydrazones/chemistry , Sulfonamides/chemistry , Animals , Antiparasitic Agents/chemical synthesis , Antiparasitic Agents/pharmacology , Cats , Dogs , Drug Discovery , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Rhipicephalus sanguineus/drug effects , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology
11.
Bioorg Med Chem ; 18(1): 222-8, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-19931462

ABSTRACT

Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimer's disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.


Subject(s)
Amyloid/antagonists & inhibitors , Amyloid/metabolism , Caseins/metabolism , Flavonoids/chemistry , Flavonoids/pharmacology , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Animals , Caseins/antagonists & inhibitors , Caseins/chemistry , Humans , Methylation , Milk/chemistry , Structure-Activity Relationship
12.
Virol J ; 6: 187, 2009 Nov 04.
Article in English | MEDLINE | ID: mdl-19889218

ABSTRACT

BACKGROUND: Using a recently described monolayer assay amenable to high throughput screening format for the identification of potential Nipah virus and Hendra virus antivirals, we have partially screened a low molecular weight compound library (>8,000 compounds) directly against live virus infection and identified twenty eight promising lead molecules. Initial single blind screens were conducted with 10 microM compound in triplicate with a minimum efficacy of 90% required for lead selection. Lead compounds were then further characterised to determine the median efficacy (IC50), cytotoxicity (CC50) and the in vitro therapeutic index in live virus and pseudotype assay formats. RESULTS: While a number of leads were identified, the current work describes three commercially available compounds: brilliant green, gentian violet and gliotoxin, identified as having potent antiviral activity against Nipah and Hendra virus. Similar efficacy was observed against pseudotyped Nipah and Hendra virus, vesicular stomatitis virus and human parainfluenza virus type 3 while only gliotoxin inhibited an influenza A virus suggesting a non-specific, broad spectrum activity for this compound. CONCLUSION: All three of these compounds have been used previously for various aspects of anti-bacterial and anti-fungal therapy and the current results suggest that while unsuitable for internal administration, they may be amenable to topical antiviral applications, or as disinfectants and provide excellent positive controls for future studies.


Subject(s)
Antiviral Agents/pharmacology , Gentian Violet/pharmacology , Gliotoxin/pharmacology , Hendra Virus/drug effects , Nipah Virus/drug effects , Quaternary Ammonium Compounds/pharmacology , Animals , Antiviral Agents/chemistry , Chlorocebus aethiops , Drug Evaluation, Preclinical , Genome, Viral/drug effects , Gentian Violet/chemistry , Gliotoxin/chemistry , Molecular Structure , Nipah Virus/genetics , Quaternary Ammonium Compounds/chemistry , Vero Cells
13.
Virus Res ; 142(1-2): 92-9, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19428741

ABSTRACT

We have recently described the development and validation of a high throughput screening assay suitable for henipavirus antiviral identification. While we are confident this assay is robust and effective, we wished to investigate assay performance in a range of alternative cell lines to determine if assay sensitivity and specificity could be improved. We evaluated ten different cell lines for their susceptibility to Hendra and Nipah virus infection and their sensitivity of detection of the effects of the broad spectrum antiviral, ribavirin and nine novel antivirals identified using our initial screening approach. Cell lines were grouped into three categories with respect to viral replication. Virus replicated best in Vero and BSR cells, followed by Hep-2, HeLa, BHK-21 and M17 cells. The lowest levels of RNA replication and viral protein expression were observed in BAEC, MMEC, A549 and ECV304 cells. Eight cell lines appeared to be similarly effective at discriminating the antiviral effects of ribavirin (<2.7-fold difference). The two cells lines most sensitive to the effect of ribavirin (ECV304 and BAEC) also displayed the lowest levels of viral replication while Vero cells were the least sensitive suggesting excess viral replication may limit drug efficacy and cell lines which limit viral replication may result in enhanced antiviral efficacy. However, there was no consistent trend observed with the other nine antivirals tested. While improvements in antiviral sensitivity in other cell lines may indicate an important role in future HTS assays, the slightly lower sensitivity to antiviral detection in Vero cells has inherent advantages in reducing the number of partially effective lead molecules identified during initial screens. Comparison of a panel of 54 novel antiviral compounds identified during routine screening of an in-house compound library in Vero, BHK-21 and BSR cells suggests no clear advantage of screening in either cell type.


Subject(s)
Antiviral Agents/pharmacology , Drug Evaluation, Preclinical/methods , Hendra Virus/physiology , Nipah Virus/physiology , Virus Replication/drug effects , Animals , Cattle , Cell Line , Chlorocebus aethiops , Guinea Pigs , Hendra Virus/drug effects , Humans , Mice , Nipah Virus/drug effects , Vero Cells
14.
Bioorg Med Chem Lett ; 18(1): 252-5, 2008 Jan 01.
Article in English | MEDLINE | ID: mdl-18006308

ABSTRACT

A series of novel 2-alkoxy- and 2-aryloxyiminoalkyl trifluoromethanesulfonanilide derivatives have shown significant in vitro parasiticidal activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. A number of these compounds also displayed significant in vitro endoparasite activity against the nematode Haemonchus contortus.


Subject(s)
Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Rhipicephalus sanguineus/drug effects , Siphonaptera/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Animals , Haemonchus/drug effects , Structure-Activity Relationship
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