195 results on '"John B. Bremner"'
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2. An investigation of the allylation cascade reactions of substituted indigos
- Author
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Matthew J. Perry, Anthony C. Willis, John B. Bremner, and Paul A. Keller
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General Chemical Engineering ,General Chemistry - Abstract
In a continuation of the exploration of indigo cascade reactions, a series of –OMe, –Ph, –Br and –NO2 substituted indigos 1a–i were synthesised to probe electronic effects upon the outcome of allylation cascade reactions.
- Published
- 2023
3. Enhancing Anticancer Potency of a 13-Substituted Berberine Derivative with Cationic Liposomes
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Nuttapon Apiratikul, Kanlayanee Sriklung, Kulvadee Dolsophon, Pattamaporn Thamvapee, Ramida Watanapokasin, Boon-ek Yingyongnarongkul, Nattisa Niyomtham, John B. Bremner, Petcharat Watanavetch, and Siritron Samosorn
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Berberine ,Doxorubicin ,Cations ,Liposomes ,Drug Discovery ,Humans ,General Chemistry ,General Medicine ,Lipids - Abstract
Cationic liposomal formulations of the telomeric G-quadruplex stabilizing ligand, 13-(2-naphthylmethoxy)berberine bromide (1), have been developed with the purpose of delivering 1 into the nucleus of cancer cells for potential telomere targeting. Berberine derivative 1 was encapsulated in various cationic lipids 2-4 by the thin film evaporation method; these lipids are cationic after amine protonation. The most appropriate liposomal berberine formulation was that of 1 and the cholesterol derived cationic lipid 4 in a weight ratio of 1 : 20 with 76.5% encapsulation efficiency of 1. Cellular uptake studies in the HeLa and HT-29 cancer cells lines showed that the liposomal berberine derivative uptake in the cells was higher and more stable than for berberine derivative 1 alone while free 1 was completely decomposed in the cells within 60 min exposure to the cells. Anticancer activity of the liposomal berberine derivative 1 based on 4 was greater than that for the free berberine derivative 1 in the MCF-7, HeLa and HT-29 cell line by 2.3-, 4.9- and 5.3-fold, respectively, and also, interestingly, superior to the anticancer drug doxorubicin against the HT29 cancer cell line.
- Published
- 2022
4. Physicochemical investigation of the enhanced removal of methylene blue from aqueous solution using polydopamine/silver nanoparticles
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Kunlanat Sriphumrat, Yutthana Wongnongwa, Siriporn Jungsuttiwong, Phakkhananan Pakawanit, Warayuth Sajomsang, John B. Bremner, and Montra Chairat
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Polymers and Plastics ,Materials Science (miscellaneous) ,General Agricultural and Biological Sciences ,Industrial and Manufacturing Engineering - Published
- 2022
5. Adsorption kinetics of lac dye on eri silk yarn
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John B. Bremner, Vatita Leamkaew, Montra Chairat, and Phattaraporn Thongsamai
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Materials science ,Polymers and Plastics ,Materials Science (miscellaneous) ,Mordant ,Yarn ,Industrial and Manufacturing Engineering ,Adsorption ,SILK ,Adsorption kinetics ,Chemical engineering ,visual_art ,visual_art.visual_art_medium ,Dyeing ,General Agricultural and Biological Sciences - Abstract
The use of natural dyes for the dyeing of naturally-derived fibres is of economic and cultural importance in many countries and there is thus ongoing research interest in this area. In the current ...
- Published
- 2021
6. An Update Review of Approaches to Multiple Action-Based Antibacterials
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John B. Bremner
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Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) ,General Pharmacology, Toxicology and Pharmaceutics ,Biochemistry ,Microbiology - Abstract
Many approaches are being pursued to address the major global health challenge posed by the increasing resistance of pathogenic bacteria to antibacterial agents. One of the promising approaches being investigated includes the design and development of multiple action-based small-molecule antibacterials. Aspects of this broad area have been reviewed previously, and recent developments are addressed in this update review covering the literature mainly over the past three years. Considerations encompassing drug combinations, single-molecule hybrids and prodrugs are summarised in regard to the intentional design and development of multiple-action agents with a focus on potential triple or greater activities in bacteria. The hope for such single agents or combinations of single agents is that resistance development will be significantly hindered, and they may be useful in tackling bacterial disease caused by both resistant and non-resistant bacteria.
- Published
- 2023
7. Computational Evaluation of N-Based Transannular Interactions in Some Model Fused Medium-Sized Heterocyclic Systems and Implications for Drug Design
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Renate Griffith and John B. Bremner
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molecular shapes ,electrostatic charges ,electron density surfaces ,Organic Chemistry ,Pharmaceutical Science ,coptisine ,protopine ,Analytical Chemistry ,Chemistry (miscellaneous) ,medium sized heterocycles ,electrostatic potentials ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,density functional theory ,transannular interactions - Abstract
As part of a project on fused medium-sized ring systems as potential drugs, we have previously demonstrated the usefulness of Density Functional Theory (DFT) to evaluate amine nitrogen-based transannular interactions across the central 10-membered ring in the bioactive dibenzazecine alkaloid, protopine. A range of related hypothetical systems have been investigated, together with transannular interactions involving ring-embedded imino or azo group nitrogens and atoms or groups (Y) across the ring. Electrostatic potential energies mapped onto electron density surfaces in the different ring conformations were evaluated in order to characterise these conformations. Unexpectedly, the presence of sp2 hybridised nitrogen atoms in the medium-sized rings did not influence the conformations appreciably. The strength and type of the N…Y interactions are determined primarily by the nature of Y. This is also the case when the substituent on the interacting nitrogen is varied from CH3 (protopine) to H or OH. With Y = BOH, very strong interactions were observed in protopine analogues, as well as in rings incorporating imino or azo groups. Strong to moderate interactions were observed with Y = CS, CO and SO in all ring systems. Weaker interactions were observed with Y = S, O and weaker ones again with an sp3 hybridised carbon (Y = CH2). The transannular interactions can influence conformational preferencing and shape and change electron distributions at key sites, which theoretically could modify properties of the molecules while providing new or enhanced sites for biological target interactions, such as the H or OH substituent. The prediction of new strong transannular interaction types such as with Y = BOH and CS should be helpful in informing priorities for synthesis and other experimental studies.
- Published
- 2023
8. Meet the Editorial Board Member
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John B. Bremner
- Subjects
Pharmacology ,Drug Discovery ,Organic Chemistry ,Molecular Medicine ,Biochemistry - Published
- 2023
9. Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1H,3′H]-3-Aryl-2,2′-diindol-3′-ones
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Nicholas M. Butler, Vicky M. Avery, John B. Bremner, Paul A. Keller, Leonardo Lucantoni, and Anthony C. Willis
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Nucleophilic addition ,010405 organic chemistry ,Aryl ,Organic Chemistry ,Indigo dye ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Desymmetrization ,Indigo ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Reagent ,Selectivity ,Natural dye - Abstract
The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition–dehydration procedure. Twenty-seven diversely functionalized [1H,3′H]-3-substituted 2,2′-diindol-3′-ones were synthesized by this methodology, with several showing submicromolar inhibition and exquisite selectivity against P. falciparum parasites (3D7 and Dd2 strains) in vitro. This work demonstrates the utility of indigo dye as a highly versatile scaffold for the synthesis of structurally diverse, bioactive heterocycles.
- Published
- 2019
10. A kinetic and thermodynamic study of lac dye adsorption on silk yarn coated with microcrystalline chitosan
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Montra Chairat, Aunlika Chimprasit, John B. Bremner, Pattarapond Gonil, Warayuth Sajomsang, and Sorasak Danworaphong
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Chemistry ,Materials Science (miscellaneous) ,General Chemical Engineering ,Dye adsorption ,Yarn ,Kinetic energy ,Chitosan ,chemistry.chemical_compound ,Microcrystalline ,SILK ,Chemical engineering ,Chemistry (miscellaneous) ,visual_art ,visual_art.visual_art_medium - Published
- 2019
11. Polydopamine‐coated silk yarn for improving the light fastness of natural dyes
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Warayuth Sajomsang, Phichet Jitjankarn, John B. Bremner, Pattarapond Gonil, Montra Chairat, and Sanhanut Kesornsit
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SILK ,Polymer science ,Chemistry (miscellaneous) ,Chemistry ,Materials Science (miscellaneous) ,General Chemical Engineering ,visual_art ,visual_art.visual_art_medium ,Yarn - Published
- 2019
12. Single Molecule Non-cleavable Multiply Active Antibacterials
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John B. Bremner
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Background information ,chemistry.chemical_compound ,Natural product ,chemistry ,Action (philosophy) ,Dual action ,Computer science ,Design elements and principles ,Molecule ,Computational biology ,Small molecule - Abstract
Multiply active non-cleavable antibacterials constitute a complex molecular design area. The emphasis in this chapter is on design parameters for small molecule triple or higher action single agents based on background information from drug combinations and dual action hybrids. Established multiple action agents or multi-targeting of bacterial sites by single ligands are discussed and then new structural possibilities are suggested illustrating the key design principles involved. A feature of this chapter is the use of a known antibacterial, the natural product berberine, as the starting point to illustrate potentially generalizable structural modifications for deliberate multiple action design. Cross referencing to sections of other chapters is included where appropriate. In this chapter there is a concentration on the medicinal chemistry aspects in new antibacterial design.
- Published
- 2021
13. Design Principles and Development of Prodrugs for Multiply Active Antibacterials
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John B. Bremner
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Chemistry ,Design elements and principles ,Antibacterial action ,Prodrug ,Combinatorial chemistry - Abstract
Added layers of complexity in design are inherent with multi-action agents released from prodrugs, and though challenging, such prodrugs do offer potential advantages over the non-cleavable multi-action hybrids. In particular the pro-moiety of the prodrug can be designed to increase solubility and permeability while the prodrug itself can enable effective delivery and site specific release of the bioactive component or components. This is particularly the case if the prodrug can be concentrated in bacteria or on their surface or in close proximity to them. The shorthand terminology ‘multiply active prodrugs’ covers compounds which need to be cleaved or activated to afford a multiply active product, or products, leading to antibacterial action. This chapter discusses known prodrugs affording multiply active products on cleavage and expands the conceptual framework to new possibilities for the design of such prodrugs. A number of release mechanisms are considered (enzymatic, chemical and physical) and implications for bacterial selectivity are explored in this Chapter.
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- 2021
14. Density functional theory assessment of transannular N⋯Y interactions in some medium-sized heterocycles
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John B. Bremner and Renate Griffith
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Physical and Theoretical Chemistry ,Condensed Matter Physics ,Biochemistry - Published
- 2022
15. The Cascade Reactions of Indigo with Propargyl Substrates for Heterocyclic and Photophysical Diversity
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John B. Bremner, Matthew J. Perry, Paul A. Keller, Timothy Clark, Dirk M. Guldi, Patrick M. McCosker, Jesse W. Mullen, Anthony C. Willis, Nicholas M. Butler, Alireza Shakoori, and Michel Volland
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010405 organic chemistry ,Chemistry ,Organic Chemistry ,Leaving group ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Fluorescence ,Catalysis ,0104 chemical sciences ,Excited state ,Electrophile ,Propargyl ,Ultrafast laser spectroscopy ,Moiety ,Density functional theory - Abstract
The synthesis of structurally diverse heterocycles for chemical space exploration was achieved via the cascade reactions of indigo with propargylic electrophiles. New pyrazinodiindolodione, naphthyridinedione, azepinodiindolone, oxazinoindolone and pyrrolodione products were prepared in one pot reactions by varying the leaving group (-Cl, -Br, -OMs, -OTs) or propargyl terminal functionality (-H, -Me, -Ph, -Ar). Mechanistic and density functional theory studies revealed that the unsaturated propargyl moiety can behave as an electrophile when aromatic terminal substitutions are made, and therefore competes with leaving group substitution for new outcomes. Selected products from the cascade reactions were investigated for their absorption and fluorescence properties, including transient absorption spectroscopy. This revealed polarity dependent excited state relaxation pathways, fluorescence, and triplet formation, thus highlighting these reactions as a means to access diverse functional materials rapidly.
- Published
- 2020
16. A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors
- Author
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Renate Griffith, Neal Dalton, Stephen G. Pyne, John B. Bremner, Nicholas Vandegraaff, Christopher P. Gordon, David Ian Rhodes, John Deadman, Paul A. Keller, and Jonathan Coates
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0301 basic medicine ,biology ,Chemistry ,Stereochemistry ,Organic Chemistry ,Human immunodeficiency virus (HIV) ,Active site ,Tripeptide ,medicine.disease_cause ,Biochemistry ,Integrase ,Core domain ,03 medical and health sciences ,030104 developmental biology ,Docking (molecular) ,Drug Discovery ,biology.protein ,medicine ,HIV Integrase Inhibitors ,Structure based - Abstract
As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC50 value of 10 ± 5 μM in HIV infected human T-cells. Additional docking of “in-house” compound libraries unearthed a methyl ester based nitrile derivative displaying an IC50 value of 0.5 μM in a combined 3′-processing and strand-transfer assay.
- Published
- 2018
17. Unexpected synthesis of 3-imino-2-(pyrrol-2-yl) isatogen derivatives affords facile access to a 2-pyrrolyl isatogen
- Author
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Anthony C. Willis, John B. Bremner, Pichit Sudta, Sunit Suksamrarn, Michael J. Kelso, Nicholas S. Kirk, and Geraud N. Sansom
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010405 organic chemistry ,Chemistry ,Stereochemistry ,Organic Chemistry ,Imine ,p-Phenylenediamine ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,Hydrolysis ,chemistry.chemical_compound ,Derivative (finance) ,Yield (chemistry) ,Reagent ,Amide - Abstract
2-Aryl isatogens and their 3-imino derivatives have been extensively studied but to date there have been no reported variants carrying pyrrolyl substituents at the 2-position. This study describes the unexpected synthesis of two novel 3-imino-2-(pyrrol-2-yl) isatogen derivatives upon attempted amide couplings with (E)- or (Z)-3-(3,5-dimethyl-1H-pyrrol-2-yl)-2-(2-nitrophenyl)acrylic acids and p-phenylenediamines in the presence of uronium-based coupling reagents. Imine hydrolysis of one derivative under mild acid conditions afforded a 2-pyrrolyl isatogen in high yield. The compound showed potent in vitro antiplasmodial activity against Plasmodium falciparum.
- Published
- 2016
18. Desymmetrization Reactions of Indigo with Grignard Reagents for the Synthesis of Selective Antiplasmodial [1
- Author
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Nicholas M, Butler, John B, Bremner, Anthony C, Willis, Leonardo, Lucantoni, Vicky M, Avery, and Paul A, Keller
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Antimalarials ,Halogens ,Indoles ,Plasmodium falciparum ,Indicators and Reagents ,Chemistry Techniques, Synthetic ,Indigo Carmine - Abstract
The nucleophilic addition of organomagnesium and organolithium species to the cheap and robust natural dye indigo led to desymmetrization of the heterocyclic nucleus via a Grignard addition-dehydration procedure. Twenty-seven diversely functionalized [1
- Published
- 2019
19. Cover Feature: The Cascade Reactions of Indigo with Propargyl Substrates for Heterocyclic and Photophysical Diversity (Chem. Eur. J. 11/2021)
- Author
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Nicholas M. Butler, Timothy Clark, Alireza Shakoori, Jesse W. Mullen, Anthony C. Willis, John B. Bremner, Dirk M. Guldi, Patrick M. McCosker, Matthew J. Perry, Michel Volland, and Paul A. Keller
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Feature (computer vision) ,Cascade ,Computational chemistry ,Chemistry ,Organic Chemistry ,Propargyl ,Cover (algebra) ,General Chemistry ,Catalysis ,Indigo - Published
- 2020
20. Biosorption of lac dye by the red marine alga Gracilaria tenuistipitata : biosorption kinetics, isotherms, and thermodynamic parameters
- Author
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John B. Bremner and Montra Chairat
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Langmuir ,Aqueous solution ,Chromatography ,biology ,Chemistry ,Materials Science (miscellaneous) ,General Chemical Engineering ,Kinetics ,Enthalpy ,Biosorption ,02 engineering and technology ,010501 environmental sciences ,021001 nanoscience & nanotechnology ,biology.organism_classification ,01 natural sciences ,Gibbs free energy ,symbols.namesake ,Chemistry (miscellaneous) ,symbols ,Freundlich equation ,0210 nano-technology ,Gracilaria ,0105 earth and related environmental sciences ,Nuclear chemistry - Abstract
The hypothesis that the dried, ground biomass of the red marine alga Gracilaria tenuistipitata could be used for the efficient removal of lac dye from aqueous solution was assessed in this work. The effects of parameters such as initial pH, biosorbent dosage, contact time, initial dye concentration, and temperature on the biosorption capacity of the dye were investigated. Equilibrium data were analysed using Langmuir, Freundlich, and Temkin isotherm models, and the Freundlich model provided the highest coefficient of determination values. Biosorption kinetic data were successfully described with a pseudo-second-order model at initial dye concentrations of 50, 80, 100, and 120 mg l−1. The thermodynamic parameters of biosorption – enthalpy change (∆H° = −30.64 kJ mol−1), free energy change (∆G° = 4.32 kJ mol−1 at 303 K to 7.78 kJ mol−1 at 333 K), and entropy change (∆S° = −115.38 J mol−1 K−1) – were determined. The negative value of the enthalpy change and positive values of the free energy change indicate that the biosorption process is exothermic and non-spontaneous. The negative value of the entropy change is consistent with decreased randomness at the solid–liquid interface with dye biosorption. Attenuated total reflectance–Fourier transform infrared spectroscopic analysis confirmed the presence of lac dye on the G. tenuistipitata material. The efficiency of lac dye removal by this biomass material at 20 g l−1 and with an initial dye concentration of 50 mg l−1 in acidic solution was 71%, which indicated its potential usefulness as a new dye biosorbent.
- Published
- 2016
21. The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction
- Author
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Christopher P. Gordon, Timothy P. Boyle, Stephen G. Pyne, Nicholas Vandegraaf, Neal Dalton, David Ian Rhodes, John B. Bremner, John Deadman, Paul A. Keller, and Jonathan Coates
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Models, Molecular ,0301 basic medicine ,Protein Conformation ,Stereochemistry ,Antimicrobial peptides ,HIV Integrase ,Tripeptide ,01 natural sciences ,Biochemistry ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,03 medical and health sciences ,Protein structure ,Structure–activity relationship ,HIV Integrase Inhibitors ,Physical and Theoretical Chemistry ,IC50 ,chemistry.chemical_classification ,Oligopeptide ,biology ,010405 organic chemistry ,Organic Chemistry ,Combinatorial chemistry ,0104 chemical sciences ,Amino acid ,Integrase ,030104 developmental biology ,chemistry ,Drug Design ,biology.protein ,Tyrosine ,Oligopeptides - Abstract
From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3'-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM.
- Published
- 2016
22. Cascade reactions of indigo with oxiranes and aziridines: efficient access to dihydropyrazinodiindoles and spiro-oxazocinodiindoles
- Author
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Anthony C. Willis, Vicky M. Avery, John B. Bremner, Rudi Hendra, Nicholas M. Butler, Paul A. Keller, and Leonardo Lucantoni
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010405 organic chemistry ,Chemistry ,Organic Chemistry ,Biological activity ,Alkylation ,010402 general chemistry ,Ring (chemistry) ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Indigo ,0104 chemical sciences ,Cascade ,Intramolecular force ,Electrophile ,Ic50 values ,Physical and Theoretical Chemistry - Abstract
The base-initiated alkylation of the abundant natural dye indigo 1 with ring-strained electrophiles results in the unprecedented, one-pot synthesis of functionalised dihydropyrazino[1,2-a:4,3-a']diindoles, dihydroepoxy[1,5]oxazocino[5,4-a:3,2-b']diindoles, and dihydrodiazepino[1,2-a:4,3-a']diindoles, resulting from intramolecular ring opening-expansion cyclisation processes of their parent oxiranes and aziridines. Regiochemical and stereochemical aspects of the reactions are reported together with integrated mechanistic proposals. This new indigo cascade chemistry should have broad applicability in the synthesis of chemical architectures, not readily-accessible by other means. The three-step synthesis of the useful synthetic precursor (R)-2-(chloromethyl)-1-tosylaziridine 14 is also described. Initial biological activity investigations into these new 2,2'-dindolyl-based heterocyclic derivatives revealed potent, selective antiplasmodial activity in vitro for several isolated structures, with IC50 values as low as 76.6 nM for (±)-8, while demonstrating low human cell toxicity.
- Published
- 2018
23. Effects of additives on the dyeing of cotton yarn with the aqueous extract of Combretum latifolium Blume stems
- Author
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Montra Chairat, Anongnet Saisara, Siritron Samosorn, Wassana Chongkraijak, Warayuth Sajomsang, and John B. Bremner
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Alum ,Materials Science (miscellaneous) ,General Chemical Engineering ,Sodium ,chemistry.chemical_element ,Mordant ,Yarn ,Pulp and paper industry ,Environmentally friendly ,Chitosan ,chemistry.chemical_compound ,chemistry ,Chemistry (miscellaneous) ,visual_art ,visual_art.visual_art_medium ,Glyoxal ,Dyeing - Abstract
Flavonoid constituents from the aqueous extract of the stems of Combretum latifolium Blume sourced in Thailand have potential use as dyestuffs for cotton dyeing. In an effort to improve current natural dyeing methods with this extract, further aspects of the process were studied. It was found that, before equilibrium was reached, an increase in temperature led to an increase in dye adsorption rate of the extract; the initial rate and extent of dye adsorption was further increased by the addition of sodium chloride to the dyebath. In addition, cotton yarn pretreated with a chitosan solution (with and without a crosslinking glyoxal solution), followed by dyeing with C. latifolium extract, provided better depth of shade and also gave better fastness to light and washing than the untreated cotton yarn. Post-mordanting cotton yarn with a biomordant solution from Memecylon scutellatum leaves also gave good light and wash fastness of the resulting dyed cotton, comparable with the dyeing results with the less environmentally friendly alum as a mordant.
- Published
- 2015
24. Further exploration of the heterocyclic diversity accessible from the allylation chemistry of indigo
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John B. Bremner, Mohammed K. Abdel-Hamid, Rachada Haritakun, Paul A. Keller, Alireza Shakoori, and Anthony C. Willis
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Olefin fiber ,Allylic rearrangement ,Chemistry ,Stereochemistry ,rearrangement ,Organic Chemistry ,cascade reactions ,Metathesis ,Full Research Paper ,Indigo ,lcsh:QD241-441 ,Claisen rearrangement ,lcsh:Organic chemistry ,Yield (chemistry) ,Rapid access ,lcsh:Q ,indigo ,nitrogen heterocycles ,lcsh:Science ,allylation - Abstract
Diversity-directed synthesis based on the cascade allylation chemistry of indigo, with its embedded 2,2’-diindolic core, has resulted in rapid access to new examples of the hydroxy-8a,13-dihydroazepino[1,2-a:3,4-b']diindol-14(8H)-one skeleton in up to 51% yield. Additionally a derivative of the novel bridged heterocycle 7,8-dihydro-6H-6,8a-epoxyazepino[1,2-a:3,4-b']diindol-14(13H)-one was produced when the olefin of the allylic substrate was terminally disubstituted. Further optimisation also produced viable one-pot syntheses of derivatives of the spiro(indoline-2,9'-pyrido[1,2-a]indol)-3-one (65%) and pyrido[1,2,3-s,t]indolo[1,2-a]azepino[3,4-b]indol-17-one (72%) heterocyclic systems. Ring-closing metathesis of the N,O-diallylic spiro structure and subsequent Claisen rearrangement gave rise to the new (1R,8aS,17aS)-rel-1,2-dihydro-1-vinyl-8H,17H,9H-benz[2',3']pyrrolizino[1',7a':2,3]pyrido[1,2-a]indole-8,17-(2H,9H)-dione heterocyclic system.
- Published
- 2015
25. Attaching the NorA Efflux Pump Inhibitor INF55 to Methylene Blue Enhances Antimicrobial Photodynamic Inactivation of Methicillin-Resistant Staphylococcus aureus in Vitro and in Vivo
- Author
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Michael R. Hamblin, John B. Bremner, Maria Magana, Ardeshir Rineh, Naveen K. Dolla, Anthony R. Ball, George P. Tegos, and Michael J. Kelso
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0301 basic medicine ,Methicillin-Resistant Staphylococcus aureus ,Indoles ,030106 microbiology ,Biology ,medicine.disease_cause ,Article ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,In vivo ,medicine ,Animals ,chemistry.chemical_classification ,Reactive oxygen species ,Mice, Inbred BALB C ,Staphylococcal Infections ,Antimicrobial ,In vitro ,Anti-Bacterial Agents ,030104 developmental biology ,Infectious Diseases ,chemistry ,Staphylococcus aureus ,Wound Infection ,Female ,Efflux ,Phototoxicity ,Methylene blue - Abstract
Antimicrobial photodynamic inactivation (aPDI) uses photosensitizers (PSs) and harmless visible light to generate reactive oxygen species (ROS) and kill microbes. Multidrug efflux systems can moderate the phototoxic effects of PSs by expelling the compounds from cells. We hypothesized that increasing intracellular concentrations of PSs by inhibiting efflux with a covalently attached efflux pump inhibitor (EPI) would enhance bacterial cell phototoxicity and reduce exposure of neighboring host cells to damaging ROS. In this study, we tested the hypothesis by linking NorA EPIs to methylene blue (MB) and examining the photoantimicrobial activity of the EPI−MB hybrids against the human pathogen methicillin-resistant Staphylococcus aureus (MRSA). Photochemical/photophysical and in vitro microbiological evaluation of 16 hybrids carrying four different NorA EPIs attached to MB via four linker types identified INF55-(Ac)en−MB 12 as a lead. Compound 12 showed increased uptake into S. aureus cells and enhanced aPDI activity and wound healing effects (relative to MB) in a murine model of an abrasion wound infected by MRSA. The study supports a new approach for treating localized multidrug-resistant MRSA infections and paves the way for wider exploration of the EPI−PS hybrid strategy in aPDI.
- Published
- 2017
26. Diarylacylhydrazones: Clostridium-selective antibacterials with activity against stationary-phase cells
- Author
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Michael J. Kelso, John B. Bremner, Naveen K. Dolla, Chao Chen, Gabriele Casadei, and Kim Lewis
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medicine.drug_class ,Clinical Biochemistry ,Antibiotics ,Pharmaceutical Science ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,Article ,Cell Line ,Microbiology ,Clostridium ,Drug Discovery ,medicine ,Humans ,Fidaxomicin ,Molecular Biology ,biology ,Clostridioides difficile ,Chemistry ,Cell Cycle ,Organic Chemistry ,Hydrazones ,Pseudomembranous colitis ,Clostridium perfringens ,Clostridium difficile ,biology.organism_classification ,Anti-Bacterial Agents ,Metronidazole ,Aminoglycosides ,Molecular Medicine ,Vancomycin ,medicine.drug - Abstract
Current antibiotics for treating Clostridium difficile infections (CDI), that is, metronidazole, vancomycin and more recently fidaxomicin, are mostly effective but treatment failure and disease relapse remain as significant clinical problems. The shortcomings of these agents are attributed to their low selectivity for C. difficile over normal gut microflora and their ineffectiveness against C. difficile spores. This Letter reports that certain diarylacylhydrazones identified during a high-throughput screening/counter-screening campaign show selective activity against two Clostridium species (C. difficile and Clostridium perfringens) over common gut commensals. Representative examples are shown to possess activity similar to vancomycin against clinical C. difficile strains and to kill stationary-phase C. difficile cells, which are responsible for spore production. Structure-activity relationships with additional synthesised analogues suggested a protonophoric mechanism may play a role in the observed activity/selectivity and this was supported by the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) showing selective anti-Clostridium effects and activity similar to diarylacylhydrazones against stationary-phase C. difficile cells. Two diarylacylhydrazones were shown to be non-toxic towards human FaDu and Hep G2 cells indicating that further studies with the class are warranted towards new drugs for CDI.
- Published
- 2014
27. Rapid Cascade Synthesis of Poly-Heterocyclic Architectures from Indigo
- Author
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John B. Bremner, Alireza Shakoori, Rachada Haritakun, Anthony C. Willis, and Paul A. Keller
- Subjects
Reaction mechanism ,Cell Survival ,Stereochemistry ,Plasmodium falciparum ,Antineoplastic Agents ,Indigo Carmine ,Ring (chemistry) ,Indigo ,Antimalarials ,Structure-Activity Relationship ,Parasitic Sensitivity Tests ,Heterocyclic Compounds ,Cell Line, Tumor ,Chlorocebus aethiops ,Animals ,Humans ,Polycyclic Compounds ,Reaction path ,Vero Cells ,Cell Proliferation ,Addition reaction ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Biological activity ,Combinatorial chemistry ,Intramolecular force ,Drug Screening Assays, Antitumor ,Selectivity - Abstract
The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a']diindole, pyrido[1,2-a:3,4-b']diindole and benzo[b]indolo[1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring B-homologue, respectively. The polycyclic compounds 6-8, whose structures were confirmed through single-crystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution-addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives indicated promising in vitro antiplasmodial activity as well as good anticancer activity. The chemistry described is new for the indigo moiety and cascade reactions from this readily available and cheap starting material should be more broadly applicable in the synthesis of additional new heterocyclic systems difficult to access by other means.
- Published
- 2013
28. ChemInform Abstract: A Cascade Synthetic Route to New Bioactive Spiroindolinepyrido[1,2-a]indolediones from Indirubin
- Author
-
Paul A. Keller, Alexander M. Sele, Renate Griffith, Rachada Haritakun, Anthony C. Willis, and John B. Bremner
- Subjects
Allylic rearrangement ,chemistry.chemical_compound ,chemistry ,Cascade reaction ,Cascade ,Isatin ,General Medicine ,Indirubin ,Cancer cell lines ,Combinatorial chemistry - Abstract
The allylation of indirubin produced the expected indolic N′-allylindirubin and N,N′-diallylindirubin derivatives in moderate yields, together with the corresponding N-substituted isatin products. At higher temperatures, the base-initiated reaction with allylic halides yielded spiroindolinepyrido[1,2-a]indolediones in a one-pot cascade reaction sequence with yields of up to 70%. These readily accessed, new spiro compounds represent the first reported examples of indirubin participating in cascade reactions. Preliminary in vitro biological testing of some of the products indicated promising activity against some cancer cell lines and against Plasmodium falciparum for two spiro derivatives. Computational methods were used to gain a greater understanding of the UV/Vis spectroscopic data for the N′-substituted and N,N′-disubstituted indirubin derivatives.
- Published
- 2016
29. On the Mechanism of Berberine-INF55 (5-Nitro-2-phenylindole) Hybrid Antibacterials
- Author
-
Michael J. Kelso, Jonah Larkins-Ford, Naveen K. Dolla, Sakthimala Jagadeesan, Rajmohan Rajamuthiah, John B. Bremner, Annie L. Conery, Chao Chen, Eleftherios Mylonakis, Frederick M. Ausubel, and Kim Lewis
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Peptide ,General Chemistry ,Combinatorial chemistry ,Article ,Multiple drug resistance ,chemistry.chemical_compound ,Berberine ,Enzyme ,chemistry ,Nitro ,Moiety ,Efflux ,Antibacterial activity - Abstract
Berberine–INF55 hybrids are a promising class of antibacterials that combine berberine and the NorA multidrug resistance pump inhibitor INF55 (5-nitro-2-phenylindole) together in one molecule via a chemically stable linkage. Previous studies demonstrated the potential of these compounds for countering efflux-mediated antibacterial drug resistance but they didn’t establish whether the compounds function as originally intended, i.e. with the berberine moiety providing antibacterial activity and the attached INF55 component independently blocking multidrug resistance pumps, thereby enhancing the activity of berberine by reducing its efflux. We hypothesised that if the proposed mechanism is correct, then hybrids carrying more potent INF55 pump inhibitor structures should show enhanced antibacterial effects relative to those bearing weaker inhibitors. Two INF55 analogues showing graded reductions in NorA inhibitory activity compared with INF55 were identified and their corresponding berberine–INF55 hybrids carrying equivalent INF55 inhibitor structures synthesised. Multiple assays comparing the antibacterial effects of the hybrids and their corresponding berberine–INF55 analogue combinations showed that the three hybrids all show very similar activities, leading us to conclude that the antibacterial mechanism(s) of berberine–INF55 hybrids is different from berberine–INF55 combinations.
- Published
- 2016
30. Binaphthyl-anchored antibacterial tripeptide derivatives with hydrophobic C-terminal amino acid variations
- Author
-
Kittiya Somphol, Jonathon A Coates, Mark J. Robertson, John B. Bremner, Paul A. Keller, Dean Baylis, John Deadman, Dharshini Jeevarajah, David Ian Rhodes, Stephen G. Pyne, and Kandasamy Sakthivel
- Subjects
VRE ,Stereochemistry ,medicine.drug_class ,Antibiotics ,Tripeptide ,medicine.disease_cause ,01 natural sciences ,Full Research Paper ,binaphthyls ,resistance ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Staphylococcus epidermidis ,cationic peptides ,medicine ,Potency ,lcsh:Science ,antibacterials ,chemistry.chemical_classification ,0303 health sciences ,biology ,010405 organic chemistry ,030306 microbiology ,Organic Chemistry ,biology.organism_classification ,In vitro ,0104 chemical sciences ,3. Good health ,Amino acid ,VISA ,Chemistry ,chemistry ,Staphylococcus aureus ,peptides ,lcsh:Q ,Bacteria - Abstract
The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2–4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.
- Published
- 2012
31. Synthesis and anti-leukaemic activity of pyrrolo[3,2,1-hi]indole-1,2-diones, pyrrolo[3,2,1-ij]quinoline-1,2-diones and other polycyclic isatin derivatives
- Author
-
Danielle Skropeta, Lidia Matesic, John B. Bremner, Kara L. Vine, Marie Ranson, and Julie M. Locke
- Subjects
Indole test ,Stereochemistry ,Isatin ,Organic Chemistry ,Quinoline ,Substituent ,Carbon skeleton ,Ring (chemistry) ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Cytotoxicity ,IC50 - Abstract
To further expand the structure–cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine- and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC50 3.01 μM) after 24 h.
- Published
- 2012
32. Targeting Urokinase and the Transferrin Receptor with Novel, Anti-Mitotic N-Alkylisatin Cytotoxin Conjugates Causes Selective Cancer Cell Death and Reduces Tumor Growth
- Author
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V. Indira Chandran, Kara L. Vine, Lidia Matesic, Julie M. Locke, Marie Ranson, J. Lee, Danielle Skropeta, and John B. Bremner
- Subjects
Isatin ,Cancer Research ,Cell Survival ,Mice, Nude ,Antineoplastic Agents ,Transferrin receptor ,Antimitotic Agents ,Biology ,Mice ,Drug Delivery Systems ,In vivo ,Cell Line, Tumor ,Receptors, Transferrin ,Drug Discovery ,medicine ,Animals ,Humans ,Cytotoxicity ,Pharmacology ,Urokinase ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Cell Death ,Cytotoxins ,U937 Cells ,Prodrug ,Urokinase-Type Plasminogen Activator ,Xenograft Model Antitumor Assays ,In vitro ,Oncology ,Biochemistry ,chemistry ,Transferrin ,Cancer cell ,Cancer research ,Female ,medicine.drug - Abstract
Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic N-alkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20(th) and 1/10(th) of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.
- Published
- 2012
33. Synthesis of new benzo[b]thieno fused ring systems via transition metal-mediated cyclisations
- Author
-
John B. Bremner, Brian W. Skelton, Johana M. Mbere, and Allan H. White
- Subjects
Indole test ,Ring-closing metathesis ,Transition metal ,Chemistry ,Stereochemistry ,Organic Chemistry ,Drug Discovery ,Ring (chemistry) ,Biochemistry - Abstract
The compact synthesis of a new ring fused benzo[b]thieno derivative with an embedded nine-membered ring system via ring closing metathesis methodology is described. The preparation of the novel 11H-benzo[b]thieno[2,3-c]pyrrolo[2,3-a]indol-11-one via palladium-mediated oxidative cyclisation of benzo[b]thien-2-oyl indole derivatives is also reported.
- Published
- 2011
34. Dyeing of cotton yarn with the aqueous extract of the leaves ofEupatorium odoratumL. in Thailand and associated extract toxicity studies
- Author
-
John B. Bremner, Montra Chairat, Udomsak Darumas, and Phuwadol Bangrak
- Subjects
chemistry.chemical_classification ,biology ,Alum ,Materials Science (miscellaneous) ,General Chemical Engineering ,Flavonoid ,Mordant ,biology.organism_classification ,Chitosan ,chemistry.chemical_compound ,chemistry ,Chemistry (miscellaneous) ,Glyoxal ,Eupatorium ,Food science ,Dyeing ,Weed - Abstract
Flavonoid constituents from the aqueous extract of the leaves of Eupatorium odoratum, an invasive weed in Thailand, have potential use as dyestuffs for cotton dyeing. It was found that cotton yarn, which was pretreated with a chitosan solution (with and without a crosslinking glyoxal solution), followed by dyeing with E. odoratum extract in the presence of the inorganic mordant, alum, provided better depth of shade (K/S) and also gave better fastness to light and washing than the untreated cotton yarn. Pretreated cotton yarn with the biomordant solution from Memecylon scutellatum leaves gave relatively poor light and wash fastness of the resultant dyed cotton in the presence of alum. From the toxicity studies, the aqueous extract of the leaves of E. odoratum before and after dyeing showed a high toxicity level to the earthworm (Diplocardia communis) and the guppy fish (Poecilia reticulate). Therefore, it is strongly suggested that E. odoratum aqueous extract after dyeing should be significantly diluted before discharged into the environment.
- Published
- 2011
35. Preclinical evaluation of novel, all-in-one formulations of 5-fluorouracil and folinic acid with reduced toxicity profiles
- Author
-
Tamantha K. Stutchbury, Kara L. Vine, Jeremy S. Chrisp, Philip Clingan, John B. Bremner, Marie Ranson, and Julie M. Locke
- Subjects
Male ,Drug ,Cancer Research ,media_common.quotation_subject ,Leucovorin ,Mice, Nude ,Breast Neoplasms ,Beta-Cyclodextrins ,Bioequivalence ,Pharmacology ,Mice ,Folinic acid ,Pharmacokinetics ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Potency ,Tissue Distribution ,Pharmacology (medical) ,media_common ,Mice, Inbred BALB C ,Dose-Response Relationship, Drug ,business.industry ,beta-Cyclodextrins ,HCT116 Cells ,Xenograft Model Antitumor Assays ,Rats ,Drug Combinations ,Oncology ,Tolerability ,Fluorouracil ,Female ,Rabbits ,Drug Screening Assays, Antitumor ,Colorectal Neoplasms ,business ,HT29 Cells ,medicine.drug - Abstract
5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations such as phlebitis and catheter blockages persist with the administration of these drugs in combination, and are associated with reduced efficacy and/or quality of life for patients. We have reported earlier on the novel, all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating β-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid. We carried out toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared with 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared with the dose-matched sequential administration of 5-FU:folinic acid. Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by the tissue distribution and pharmacokinetic studies of 5-FU, but was generally better tolerated as determined by weight loss, hematological, and other clinical parameters. Compared with 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, using human carcinoma tumor models in mice, Fluorodex resulted in equivalent or improved efficacy profiles compared with 5-FU:folinic acid. In conclusion, these novel, all-in-one formulations represent a superior injectable form of 5-FU that allows codelivery of folinic acid. This should translate into improved patient tolerability with potential for enhanced efficacy.
- Published
- 2011
36. Antiplasmodial activity of atisinium chloride from the Bhutanese medicinal plant, Aconitum orochryseum
- Author
-
Brian W. Skelton, John B. Bremner, Samten, Sumalee Kamchonwongpaisan, Roonglawan Rattanajak, Phurpa Wangchuk, and Allan H. White
- Subjects
Pharmacology ,Aconitum ,biology ,Traditional medicine ,Plant Extracts ,Alkaloid ,Plasmodium falciparum ,Absolute configuration ,Ranunculaceae ,Plant Components, Aerial ,Pharmacognosy ,Crystallography, X-Ray ,biology.organism_classification ,Terpenoid ,Antimalarials ,Inhibitory Concentration 50 ,Alkaloids ,Drug Discovery ,Medicine, Traditional ,Diterpenes ,Bhutan ,Medicinal plants - Abstract
Ethnopharmacological relevance The plant Aconitum orochryseum Stapf. (Ranunculaceae) is employed together with other plants in Bhutanese traditional medicine and is indicated for malaria-associated fever. Aim of the study To study the in vitro antiplasmodial activity of atisinium chloride, the major alkaloid from Aconitum orochryseum . Materials and methods Atisinium chloride was extracted and purified from aerial parts of Aconitum orochryseum and its structure and absolute configuration confirmed by single crystal X-ray crystallography. The crude methanol extract, crude alkaloid fraction, and atisinium chloride were tested for in vitro antiplasmodial activity against the malarial Plasmodium falciparum strains TM4/8.2 (TM4; wild type) and K1CB1 (K1; chloroquine and antifolate resistant). Results The diterpenoid alkaloid atisinium chloride was shown to have moderate antiplasmodial activities with IC 50 values of 4 μM and 3.6 μM, respectively against the TM4 strain and the K1 strain of Plasmodium falciparum . Conclusions Our studies provide the first evidence in support of one of the indicated treatments with Aconitum orochryseum in Bhutanese traditional medicine. This alkaloid also represents a potential new antimalarial structural lead.
- Published
- 2010
37. Berberine-INF55 (5-Nitro-2-Phenylindole) Hybrid Antimicrobials: Effects of Varying the Relative Orientation of the Berberine and INF55 Components
- Author
-
Kim Lewis, Michael J. Kelso, John B. Bremner, Gabriele Casadei, Frederik M Ausubel, Danuta Tomkiewicz, Terence I. Moy, Jonah Larkins-Ford, and James Garner
- Subjects
Staphylococcus aureus ,Indoles ,Berberine ,Stereochemistry ,Microbial Sensitivity Tests ,Biology ,medicine.disease_cause ,Structure-Activity Relationship ,chemistry.chemical_compound ,Bacterial Proteins ,Drug Resistance, Multiple, Bacterial ,Ethidium ,Enterococcus faecalis ,medicine ,Animals ,Structure–activity relationship ,Pharmacology (medical) ,Caenorhabditis elegans ,Mechanisms of Action: Physiological Effects ,Pharmacology ,Antiinfective agent ,Molecular Structure ,Alkaloid ,Anti-Bacterial Agents ,Multiple drug resistance ,Infectious Diseases ,Biochemistry ,chemistry ,Drug Design ,Efflux ,Multidrug Resistance-Associated Proteins ,Ethidium bromide - Abstract
Hybrid antimicrobials containing an antibacterial linked to a multidrug resistance (MDR) pump inhibitor make up a promising new class of agents for countering efflux-mediated bacterial drug resistance. This study explores the effects of varying the relative orientation of the antibacterial and efflux pump inhibitor components in three isomeric hybrids (SS14, SS14-M, and SS14-P) which link the antibacterial alkaloid and known substrate for the NorA MDR pump berberine to different positions on INF55 (5-nitro-2-phenylindole), an inhibitor of NorA. The MICs for all three hybrids against wild-type, NorA-knockout, and NorA-overexpressing Staphylococcus aureus cells were found to be similar (9.4 to 40.2 μM), indicating that these compounds are not effectively effluxed by NorA. The three hybrids were also found to have similar curing effects in a Caenorhabditis elegans live infection model. Each hybrid was shown to accumulate in S. aureus cells to a greater extent than either berberine or berberine in the presence of INF55, and the uptake kinetics of SS14 were found to differ from those of SS14-M and SS14-P. The effects on the uptake and efflux of the NorA substrate ethidium bromide into S. aureus cells in the presence or absence of the hybrids were used to confirm MDR inhibition by the hybrids. MDR-inhibitory activity was confirmed for SS14-M and SS14-P but not for SS14. Molecular dynamics simulations revealed that SS14 prefers to adopt a conformation that is not prevalent in either SS14-M or SS14-P, which may explain why some properties of SS14 diverge from those of its two isomers. In summary, subtle repositioning of the pump-blocking INF55 moiety in berberine-INF55 hybrids was found to have a minimal effect on their antibacterial activities but to significantly alter their effects on MDR pumps.
- Published
- 2010
38. Equilibrium and kinetic modeling of the adsorption of indigo carmine onto silk
- Author
-
John B. Bremner, Vichitr Rattanaphani, Saowanee Rattanaphani, and Naparat Jiwalak
- Subjects
Langmuir ,Polymers and Plastics ,Chemistry ,General Chemical Engineering ,Enthalpy ,Thermodynamics ,Langmuir adsorption model ,General Chemistry ,Indigo ,symbols.namesake ,chemistry.chemical_compound ,Adsorption ,Indigo carmine ,symbols ,Physical chemistry ,Freundlich equation ,Dyeing - Abstract
Quantitative adsorption kinetic and equilibrium parameters for indigo carmine dyeing of silk were studied using UV-visible absorption spectroscopy. The effect of initial dye concentration, contact time, pH, material to liquor ratio (MLR), and temperature were determined to find the optimal conditions for adsorption. The mechanism of adsorption of indigo carmine dyeing onto silk was investigated using the pseudo first-order and pseudo second-order kinetic models. The adsorption kinetics was found to follow a pseudo-second-order kinetic model with an activation energy (E a) of 51.06 kJ/mol. The equilibrium adsorption data of indigo carmine dye on silk were analyzed by the Langmuir and Freundlich models. The results indicate that the Langmuir model provides the best correlation. Adsorption isotherms were also used to obtain thermodynamic parameters such as free energy (ΔG o), enthalpy (ΔH o), and entropy (ΔS o) of adsorption. The negative values of ΔG o and ΔH o indicate the overall adsorption process is a spontaneous and exothermic one.
- Published
- 2010
39. Novel spiro and fused heterocycles from the allylation of indigo
- Author
-
Allan H. White, John B. Bremner, Brian W. Skelton, Paul A. Keller, Jonathan Coates, Yasmine S. Torkamani, Mohammed K. Abdel-Hamid, Anthony C. Willis, and Celia Miländer
- Subjects
chemistry.chemical_classification ,Chemical structure ,Organic Chemistry ,One-pot synthesis ,Biochemistry ,Combinatorial chemistry ,Indigo ,chemistry.chemical_compound ,Cascade reaction ,chemistry ,Indigo carmine ,Heterocyclic compound ,Microwave heating ,Drug Discovery ,Microwave irradiation ,Organic chemistry - Abstract
The allylation of indigo results in the one-step synthesis of two unique complex heterocyclic systems: a spiroindoline–pyridoindolone arising from the addition of three allyl moieties and a fused pyridoindolo-azepinoindolone generated from the addition and subsequent cyclisation of two allyl moieties. The structures of these novel heterocycles are assigned unambiguously using extensive NMR experiments and by X-ray crystallographic analysis. The distribution of the products is influenced by the use of thermal versus microwave heating.
- Published
- 2009
40. Development and assessment of novel all-in-one parenteral formulations with integrated anticoagulant properties for the concomitant delivery of 5-fluorouracil and calcium folinate
- Author
-
Philip Clingan, Kara L. Vine, John B. Bremner, Marie Ranson, Tamantha K. Stutchbury, Allan B. Gamble, and Julie M. Locke
- Subjects
Antimetabolites, Antineoplastic ,Cancer Research ,medicine.drug_class ,Chemistry, Pharmaceutical ,Leucovorin ,Pharmacology ,Excipients ,Mice ,Folinic acid ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Potency ,Thromboplastin ,Infusions, Parenteral ,Pharmacology (medical) ,Cytotoxicity ,Cell Proliferation ,chemistry.chemical_classification ,Cyclodextrins ,Mice, Inbred BALB C ,Cyclodextrin ,business.industry ,Anticoagulant ,Anticoagulants ,In vitro ,Drug Combinations ,Oncology ,chemistry ,Fluorouracil ,Female ,business ,medicine.drug - Abstract
5-Fluorouracil in combination with its biomodulator folinic acid maintains a pivotal position in current anticancer treatment regimens. However, limitations in clinical management persist with the administration of these drugs. These limitations are associated with the use of a high pH to maintain 5-fluorouracil in solution, resulting in high rates of phlebitis and catheter blockages. Herein, we describe and compare initial studies on novel all-in-one formulations of 5-fluorouracil and folinic acid incorporating either sulfated or hydroxypropyl beta-cyclodextrins at physiological pH that potentially address these issues. All formulations markedly improved the stability of supersaturated solutions of 5-fluorouracil in the presence of folinic acid. In-vitro evaluation of the PC-3, HCT-116, MDA-MB-231, PC-14, and COLO-201 human carcinoma cell lines showed that all formulations exhibited equivalent or better cytotoxicity compared with cells exposed to 5-fluorouracil and folinic acid. Thus, these cyclodextrins do not compromise the cytotoxicity of 5-fluorouracil. Preliminary in-vivo dose tolerance profiles of the formulations were also equivalent to 5-fluorouracil and folinic acid administered separately. Furthermore, given the association between thrombosis and cancer, the potentially beneficial anticoagulant activity of the sulfated cyclodextrin-based formulations was also confirmed in vitro. Extended activated partial thromboplastin times and prothrombin times were observed for the sulfated cyclodextrins in human plasma both as individual compounds and as components of the formulations. In conclusion, these novel all-in-one formulations maintain the in-vitro potency while overcoming the accepted incompatibility of 5-fluorouracil and folinic acid, and represent improved injectable forms of 5-fluorouracil that may reduce phlebitis, catheter blockages, and thromboembolic events.
- Published
- 2009
41. An adsorption study of alum-morin dyeing onto silk yarn
- Author
-
John B. Bremner, Saowanee Rattanaphani, Chutima Septhum, and Vichitr Rattanaphani
- Subjects
Materials science ,Polymers and Plastics ,Alum ,General Chemical Engineering ,Enthalpy ,Mordant ,General Chemistry ,Morin ,Activation energy ,chemistry.chemical_compound ,Adsorption ,SILK ,chemistry ,Polymer chemistry ,Dyeing ,Nuclear chemistry - Abstract
Silk yarn was dyed with morin (2′,3,4′,5,7-pentahydroxyflavone) by using alum as mordant. In order to optimize the process, three methods of dyeing involving: pre-mordanting, simultaneous mordanting, and post-mordanting were assessed and compared with a mordant-free process. The adsorption of alum-morin dye onto silk fibers indicated that the adsorption capacities were significantly affected by pH, the initial dye concentration, and temperature. The initial dye adsorption rates of alum-morin dye on silk before equilibrium was reached increased with higher dyeing temperatures. The pseudo second-order kinetic model was indicated for alum-morin dyeing (simultaneous mordanting) of silk at pH 4.0 with an activation energy (Ea) of 45.26 kJ/mol. The value of the enthalpy of activation (ΔH#) for alum-morin dyeing on silk at pH 4.0 was −31.29 kJ/mol. Also, the free energy (ΔGo) and entropy changes (ΔSo) for alum-morin dyeing on silk were −17.73 kJ/mol and −45.7 J/molK, respectively, consistent with a spontaneous and exothermic adsorption process.
- Published
- 2009
42. Antiplasmodial agents from the Bhutanese medicinal plant Corydalis calliantha
- Author
-
John B. Bremner, Roonglawan Rattanajak, Samten, Sumalee Kamchonwongpaisan, and Phurpa Wangchuk
- Subjects
Pharmacology ,Traditional medicine ,biology ,Alkaloid ,Plasmodium falciparum ,Corydalis ,Pharmacognosy ,biology.organism_classification ,Multiple drug resistance ,chemistry.chemical_compound ,chemistry ,Scoulerine ,Protopine ,heterocyclic compounds ,Medicinal plants - Abstract
The alkaloidal components of the Bhutanese medicinal plant Corydalis calliantha Long, which is used for the treatment of malaria, have been assessed. Four known alkaloids, protopine (1), scoulerine (2), cheilanthifoline (3) and stylopine (4) are reported from this plant for the first time. The protopine alkaloid, protopine, and the tetrahydroprotoberine alkaloid, cheilanthifoline, showed promising in vitro antiplasmodial activities against Plasmodium falciparum, both wild type (TM4) and multidrug resistant (K1) strains with IC(50) values in the range of 2.78-4.29 microM. Such activity had not been demonstrated previously for cheilanthifoline. The results thus support, at a molecular level, the clinical use of this plant in the Bhutanese traditional medicine and identified cheilanthifoline as a potential new antimalarial drug lead.
- Published
- 2009
43. Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group
- Author
-
John B. Bremner, Jennifer L. Beck, Danuta Tomkiewicz, Bongkot Tanwirat, Karina C. Gornall, Therdsak Prammananan, Nussara Muhamad, Siritron Samosorn, Kim Lewis, Gabriele Casadei, and Apichart Suksamrarn
- Subjects
Staphylococcus aureus ,Indoles ,Berberine ,Stereochemistry ,Clinical Biochemistry ,Nitro compound ,Pharmaceutical Science ,Ether ,Biochemistry ,Article ,chemistry.chemical_compound ,Bacterial Proteins ,Drug Discovery ,Enterococcus faecalis ,Methylene ,Molecular Biology ,Antibacterial agent ,chemistry.chemical_classification ,Molecular Structure ,Alkaloid ,Organic Chemistry ,Intercalating Agents ,Anti-Bacterial Agents ,chemistry ,Molecular Medicine ,Efflux ,Multidrug Resistance-Associated Proteins ,Antibacterial activity - Abstract
Conjugation of the NorA substrate berberine and the NorA inhibitor 5-nitro-2-phenyl-1H-indole via a methylene ether linking group gave the 13-substituted berberine-NorA inhibitor hybrid, 3. A series of simpler arylmethyl ether hybrid structures were also synthesized. The hybrid 3 showed excellent antibacterial activity (MIC Staphylococcus aureus, 1.7 microM), which was over 382-fold more active than the parent antibacterial berberine, against this bacterium. This compound was also shown to block the NorA efflux pump in S. aureus.
- Published
- 2009
44. Novel technique shows different hydrophobic chemical signatures of exotic and indigenous plant soils with similar effects of extracts on indigenous species seedling growth
- Author
-
Emilie-Jane Ens, John B. Bremner, Jurgen Korth, and Kristine French
- Subjects
biology ,Seedling ,Botany ,Soil Science ,Soil chemistry ,Acacia ,Soil classification ,Introduced species ,Plant Science ,Acacia longifolia ,Chrysanthemoides monilifera ,biology.organism_classification ,Soil type - Abstract
Changes to ecosystem abiotic parameters are regarded as possible mechanisms facilitating plant invasion and community composition shifts. This study compared the hydrophobic chemical signatures of soil from exotic bitou bush (Chrysanthemoides monilifera spp. rotundata) invaded, indigenous acacia (Acacia longifolia var. sophorae) dominated and bare sand (unvegetated) habitats using a novel, rapid, capturing technique which utilised Amberlite® XAD4 resin filled bags that were placed in situ. The hydrophobic chemical signature of the bitou bush soil extract was significantly different to the acacia soil and bare sand extracts. High concentrations of 18 sesquiterpenes dominated the hydrophobic signature of the bitou bush extract. Low concentrations of all three extracts did not significantly affect the seedling growth of three indigenous test species under laboratory conditions, however, at higher concentrations, the extracts from soil inhabited by plants, whether exotic or indigenous, similarly inhibited the seedling growth of two species, while seedling growth of the third species was inhibited by extracts from all three soil types. These results do not support the hypothesis that exotic invasive species are more likely to exhibit allelopathic effects than indigenous plant species.
- Published
- 2009
45. Synthesis of novel N-protected hydrophobic phenylalanines and their application in potential antibacterials
- Author
-
John Deadman, John B. Bremner, Kittiya Somphol, Paul A. Keller, Jonathan Coates, Timothy P. Boyle, and Stephen G. Pyne
- Subjects
Pharmacology ,chemistry.chemical_classification ,Spectrometry, Mass, Electrospray Ionization ,Staphylococcus aureus ,Magnetic Resonance Spectroscopy ,Tetrapeptide ,Stereochemistry ,Phenylalanine ,Organic Chemistry ,Cationic polymerization ,Peptoid ,Peptide ,Microbial Sensitivity Tests ,General Medicine ,Tripeptide ,Chemical synthesis ,Anti-Bacterial Agents ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Lipophilicity ,Antibacterial agent - Abstract
An efficient synthesis of two new N -acetyl-4′-arylphenylalanines is described together with their incorporation into a number of cationic peptoid antibacterial agents, one of which had an MIC of 7.8 μg/mL against Staphylococcus aureus .
- Published
- 2009
46. A Facile Approach to 2-Substituted Isoflav-3-enes via Isoflavylium Salts
- Author
-
John B. Bremner, Renate Griffith, Andrew Heaton, and Jane Faragalla
- Subjects
chemistry.chemical_compound ,chemistry ,Nucleophile ,Hydride ,Hexafluorophosphate ,Organic Chemistry ,Regioselectivity ,Medicinal chemistry - Abstract
A compact and regioselective approach to 2-substituted isoflav-3-enesbased on a preformed 2-unsubstituted isoflavene is described. Isoflaveneoxidation by hydride ion abstraction to the corresponding isoflavyliumsalt using trityl hexafluorophosphate followed by nucleophilic additionto the 2-position resulted in the introduction of a range of substituentgroups in generally moderate to good yields.
- Published
- 2009
47. New cyclic peptides via ring-closing metathesis reactions and their anti-bacterial activities
- Author
-
David Ian Rhodes, John B. Bremner, Timothy P. Boyle, Stephen G. Pyne, Paul A. Keller, Jonathan Coates, and John Deadman
- Subjects
chemistry.chemical_classification ,Dipeptide ,Allylglycine ,Organic Chemistry ,medicine.disease_cause ,Metathesis ,Biochemistry ,Combinatorial chemistry ,Cyclic peptide ,chemistry.chemical_compound ,Ring-closing metathesis ,chemistry ,Staphylococcus aureus ,Drug Discovery ,medicine ,Salt metathesis reaction ,Tyrosine - Abstract
As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring-closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 μg/mL.
- Published
- 2008
48. Evidence for allelopathy as a mechanism of community composition change by an invasive exotic shrub, Chrysanthemoides monilifera spp. rotundata
- Author
-
John B. Bremner, Emilie-Jane Ens, and Kris French
- Subjects
biology ,ved/biology ,ved/biology.organism_classification_rank.species ,Soil Science ,Acacia ,Plant community ,Plant Science ,Chrysanthemoides monilifera ,biology.organism_classification ,Shrub ,Invasive species ,Chrysanthemoides ,Botany ,Acacia longifolia ,Allelopathy - Abstract
Chemical interference is increasingly suggested as a mechanism facilitating exotic plant invasion and plant community composition. In order to explore this further, we employed a comprehensive extract-bioassay technique that facilitated detection and demarcation of phytotoxicity, direct allelopathy and indirect allelopathy of bitou bush (Chrysanthemoides monilifera spp. rotundata) compared to an indigenous dominant of the invaded system, acacia (Acacia longifolia var. sophorae). Extracts of the leaves and roots of both species exhibited phytotoxic effects against five indigenous plant species. Evidence for allelopathy between co-evolved indigenous plants was detected between acacia and Isolepis nodosa. Allelopathy between bitou bush and four indigenous plant species was also detected. Therefore we propose that both the acacia and bitou bush have the potential to chemically inhibit the establishment of indigenous plants. Eventual dominance of bitou bush is predicted, however, based on more ubiquitous effects on seedling growth.
- Published
- 2008
49. Structure–activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus
- Author
-
Anthony R. Ball, John B. Bremner, Joseph I. Ambrus, Michael J. Kelso, Gabriele Casadei, and Kim Lewis
- Subjects
Staphylococcus aureus ,Indoles ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Clinical Biochemistry ,Nitro compound ,Pharmaceutical Science ,medicine.disease_cause ,Biochemistry ,Chemical synthesis ,Article ,Structure-Activity Relationship ,Electrophilic substitution ,chemistry.chemical_compound ,Bacterial Proteins ,Ciprofloxacin ,Drug Discovery ,medicine ,Combinatorial Chemistry Techniques ,Rhodium ,Molecular Biology ,Antibacterial agent ,chemistry.chemical_classification ,Indole test ,Molecular Structure ,Chemistry ,Organic Chemistry ,Anti-Bacterial Agents ,Drug Design ,Molecular Medicine ,Efflux ,Multidrug Resistance-Associated Proteins ,Lead compound ,Palladium - Abstract
The synthesis of 22 2-aryl-1H-indoles, including 12 new compounds, has been achieved via Pd- or Rh-mediated methodologies, or selective electrophilic substitution. All three methods were based on elaborations from simple indole precursors. SAR studies on these indoles and 2-phenyl-1H-indole in Staphylococcus aureus as NorA efflux pump inhibitors indicated 5-nitro-2-(3-methoxycarbonyl)phenyl-1H-indole was a slightly more potent inhibitor than the lead INF55. A promising new antibacterial lead compound against S. aureus (2-phenyl-1H-indol-5-yl)-methanol, was also found.
- Published
- 2008
50. A Compact Approach to an Isomeric Iheyamine A System and X-ray Crystal Structure of 5-Methyl-5H-azepino[2,3- b :4,5- b ′]diindole
- Author
-
Waya Sengpracha, John B. Bremner, and Brian W. Skelton
- Subjects
Crystal ,chemistry.chemical_compound ,Crystallography ,Natural product ,chemistry ,Stereochemistry ,Product (mathematics) ,Organic Chemistry ,X-ray ,Crystal structure - Abstract
A compact three-step synthesis of a new fused bisindole system isomeric with the heterocyclic skeleton present in the marine natural product iheyamine A has been achieved. The structure of the synthetic product was confirmed by a single-crystal X-ray structure.
- Published
- 2008
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