Physical Sciences and Mathematics | Open Access Articles

Synthesis Of Reaction-Ready 6,6 '-Biindole And 6,6 '-Biisatin Via Palladium(Ii)-Catalysed Intramolecular C-H Functionalisation, Allan B. Gamble, Paul A. Keller

Paul Keller

The first synthesis of a 6,6'-biindole and 6,6'-biisatin scaffold is reported with the penultimate step being the formation of the di-heterocyclic ring by Pd(II)-catalysed intramolecular C-H functionalisation and Sandmeyer cyclisation, respectively.

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The First Syntheses Of Enantiopure 2,2 '-Biindoline, Steven M. Wales, Anthony C. Willis, Paul A. Keller

Paul Keller

The first two syntheses of chiral 2,2'-biindoline are reported either in five steps from 2,2'-bioxirane, or three steps from 2,2'-biaziridine, both with exceptional enantiopurity

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Reductive Ring Opening Reactions Of Diphenyldihydrofullerenylpyrroles, William Hawkins, Paul A. Keller, Stephen G. Pyne

Paul Keller

The reductive ring opening reaction conditions for the simple [60]fullerenyldihydropyrrole 1 have been optimized to include acetic acid in the reaction mixture to rapidly protonate the anionic intermediate. Under these conditions, the ring opened dihydrofullerene 2 was obtained in 68% yield. Under slightly modified conditions and at −78 °C, the reductive bis-ring opening of the tethered trans-4 isomer 3 provided the novel racemic bis-dihydrofullerenyl derivative 7.

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Revealing Indigenous Indonesian Traditional Medicine: Anti-Infective Agents, Paul A. Keller, Ari Satia Nugraha

Paul Keller

Indonesia is rich in medicinal plants which the population has used traditionally from generation to generation for curing diseases. Our interest in the treatment of infectious diseases has lead to the investigation of traditional Indonesian treatments. In this review, we present a comprehensive review of ethnopharmacologically directed screening in Indonesian medicinal plants to search for new anti-viral, antimalarial, anti-bacterial and anti-fungal agents. Some potent drug leads have been isolated from Indonesian medicinal plants. Further research is still required for the lead development as well as the search for new bioactive compounds from the enormous medicinal plant resources.

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Binaphthyl-Anchored Antibacterial Tripeptide Derivatives With Hydrophobic C-Terminal Amino Acid Variations, John Bremner, Paul A. Keller, Stephen Pyne, Mark Robertson, Kandasamy Sakthivel, Kittiya Somphol, Dean Baylis, Jonathon A Coates, John Deadman, Dharshini Jeevarajah, David I. Rhodes

Paul Keller

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.

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Synthesis Of Novel N-Protected Hydrophobic Phenylalanines And Their Application In Potential Antibacterials, Timothy P. Boyle, J. B. Bremner, Jonathan A. Coates, John Deadman, Paul A. Keller, Stephen G. Pyne, Kittiya Somphol

Paul Keller

An efficient synthesis of two new N-acetyl-4’-arylphenylalanines is described together with their incorporation in to a number of cationic peptoid antibacterial agents, one of which had an MIC of 7.8 μg/mL against Staphylococcus aureus.

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Phytochemical And Biological Activity Studies Of The Bhutanese Medicinal Plant Corydalis Crispa, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Thanapat Sastraruji, Malai Taweechotipatr, Roonglawan Rattanajak, Aunchalee Tonsomboon, Sumalee Kamchonwongpaisan

Paul Keller

The chemical constituents and biological activities of Corydalis crispa (Fumariaceae) were investigated for the first time. The phytochemical study resulted in the isolation of nine known isoquinoline alkaloids: protopine (1), 13-oxoprotopine (2), 13-oxocryptopine (3), stylopine (4), coreximine (5), rheagenine (6), ochrobirine (7), sibiricine (8) and bicuculline (9), with complete NMR data for 2 and 3 provided here for the first time. Crude extracts exhibitedsignificant anti-inflammatory (p < 0.01) activity against TNF-alpha production in LPS activated THP-1 cells. The acetylcholinesterase inhibitory activity of compounds 2, 4 and 7 and the antiplasmodial activity of compound 5 against P. falciparum strains TM4/8.2 and K1CB1 …

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Antimalarial Alkaloids From A Bhutanese Traditional Medicinal Plant Corydalis Dubia, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Anthony C. Willis, Sumalee Kamchonwongpaisan

Paul Keller

Ethnopharmacological relevance: Corydalis dubia is used in Bhutanese traditional medicine as a febrifuge and for treating infections in the blood, liver and bile which correlate to the signs and symptoms of malarial and microbial infections. Aim of the study: To validate the ethnopharmacological uses of the plant and to discover potential new therapeutic drug leads. Materials and methods C. dubia was collected from Bhutan and the alkaloids were obtained using acid–base fractionation and separation by repeated column and preparative plate chromatography. The alkaloids were identified from analysis of their physiochemical and spectroscopic data and were tested for antiplasmodial, antimicrobial and …

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Structural Re-Assignment Of The Mono- And Bis-Addition Products From The Addition Reactions Of N-(Diphenylmethylene)Glycinate Esters To [60]Fullerene Under Bingel Conditions, Graham E Ball, Glenn Ashley Burley, Leila Chaker, William Hawkins, James Williams, Paul A. Keller, Stephen G. Pyne

Paul Keller

The addition of N-(diphenylmethylene)glycinate esters (Ph₂C=NCH₂CO₂R) to [60]fullerene under Bingel conditions gives [60]fullerenyldihydropyrroles and not methano[60]fullerenyl iminoesters [C₆₀C(CO₂R)(N=CPh₂)] as previously reported. Unequivocal evidence for the structure of C₆₀C(CO₂Et)(N=CPh₂) was provided by INADEQUATE NMR studies on ¹³C enriched material. New mechanistic details are proposed to account for the formation of [60]fullerenyldihydropyrroles and their reductive ring-opening reactions.

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Synthesis And In Vitro Binding Of N,N-Dialkyl-2-Phenylindol-3-Ylglyoxylamides For The Peripheral Benzodiazepine Binding Sites, T. P. Homes, F. Mattner, Paul A. Keller, A. Katsifis

Paul Keller

A series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes were evaluated using [3H]-PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using 3H-flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC50) ranging from 7.86 nM to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC50 > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS …

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Synthesis Of Some Cyclic Indolic Peptoids As Potential Antibacterials, Vicki S. Au, John B. Bremner, Jonathan Coates, Paul A. Keller, Stephen G. Pyne

Paul Keller

The synthesis of cyclic peptoids containing an indole hydrophobic scaffold has been realised through the ring-closing metathesis of diallylated precursors. The precursors and their cyclic counterparts possessed poor antibacterial activity in contrast to previously reported cyclic peptoids containing hydrophobic scaffolds.

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[60]Fullerene Amino Acids And Related Derivatives, Glenn A. Burley, Paul A. Keller, Stephen G. Pyne

Paul Keller

This paper is a review of the literature concerning the preparation of [60]fullerene amino acid and peptide derivatives. The structure and applications of these derivatives to the biological and material sciences is also presented.

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Reactions Of Iminoglycines With C60 Fullerene And Their Unambiguous Characterisation Using Nmr Spectroscopy, Paul A. Keller, Stephen G. Pyne, Bill C. Hawkins

Paul Keller

This review examines the addition of iminoglycine derivatives to C60, yielding protected fullerenyl pyrroline derivatives. Subsequent reduction with sodium cyanoborohydride produces ring-opening adducts which are protected fullerenyl α-amino acids. Pyrroline bisadducts can be produced using tethers to link two iminoglycine units together, and variations include combining with malonate reactive groups this giving rise to interesting observations as to the regioselectivity of such reactions. All derivatives are fully characterised by NMR spectroscopy, and in the case of bis-adducts, the regioselectivity is determined from 1H/13C and 13C/13C connectivity patterns using HMBC and INADEQUATE experiments, respectively, thus eliminating the need for comparative techniques …

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New Cyclic Peptides Via Ring-Closing Metathesis Reactions And Their Anti-Bacterial Activities, Timothy P. Boyle, John B. Bremner, Jonathan Coates, John Deadman, Paul A. Keller, Stephen G. Pyne, David I. Rhodes

Paul Keller

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.

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Regioselective Synthesis Of Novel E-Edge-[60]Fullerenylmethanodihydropyrroles And 1,2-Dihydromethano[60]Fullerenes, Leila Chaker, Graham E. Ball, James R. Williams, Glenn A. Burley, Bill C. Hawkins, Paul A. Keller, Stephen G. Pyne

Paul Keller

Treatment of a tethered N-(diphenylmethylene)glycinate-malonate derivative with [60]fullerene under Bingel conditions yielded an e-edge-[60]fullerenylmethanodihydropyrrole adduct in a regioselective manner. The regiochemical outcome was independent of the order of addition of either the N-(diphenylmethylene)glycinate or the malonate moieties. This new bis-adduct was also prepared in 13C enriched form allowing for its unequivocal structural characterization by 2D INADEQUATE NMR experiments. Ring-opening of the dihydropyrrole functionality of the bisadducts under reductive conditions gave exclusively novel dihydromethano[60]fullerene derivatives.

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The Role Of The Hpa Axis In Psychiatric Disorders And Crf Antagonists As Potential Treatments, Paul A. Keller, A. Mccluskey, J. Morgan, S. M. O'Connor

Paul Keller

An overview of the links between the Hypothalamic-Pituitary-Adrenal (HPA) axis and psychiatric disorders is presented. The current treatments are outlined, indicating that they are insufficient to meet the needs of those that suffer from these affective disorders. Therefore, there is an urgent need for the generation of new therapeutics, in particular, against new targets. The association of the corticotrophin releasing factor (CRF) and the HPA axis indicates that CRF antagonists should be beneficial as potential therapeutics.

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A Convenient And Efficient Synthesis Of (S)-Lysine And (S)-Arginine Homologues Via Olefin Cross-Metathesis, Timothy P. Boyle, John B. Bremner, Jonathan A. Coates, Paul A. Keller, Stephen G. Pyne

Paul Keller

A convenient five step synthesis of (S)-homolysine, incorporating a key olefin cross-metathesis step in the chain extension methodology, has been developed, together with a six step related synthesis of a new homologue of arginine, (S)-bishomoarginine.

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Antimalarial Activity Of 2,4-Diaminopyrimidines, J. Morgan, R. Haritakul, Paul A. Keller

Paul Keller

A series of 2,4- and 4,6-diaminopyrimidines were prepared and evaluated for their in vitro antimalarial activity. Of the 12 compounds tested 7 showed reasonable activity with 1 having a sub-micromolar IC50.

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Aryl Nitro Reduction With Iron Powder Or Stannous Chloride Under Ultrasonic Irradiation, A. B. Gamble, James A. Garner, Christopher Gordon, S. M. J. O'Conner, Paul A. Keller

Paul Keller

The selective reduction of aryl nitro compounds in the presence of sensitive functionalities, including halide, carbonyl, nitrile and ester substituents under ultrasonic irradiation at 35 kHz is reported in yields of 39-98%. Iron powder proved superior to stannous chloride with high tolerance of sensitive functional groups and high yields of the desired aryl amines in relatively short reaction times. Simple experimental procedure and purification also make the iron reduction of aryl nitro compounds advantageous over other methods of reduction.

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Control Of Hiv Through The Inhibition Of Hiv-1 Integrase: A Medicinal Chemistry Perspective, Christopher Gordon, R. Griffith, Paul A. Keller

Paul Keller

This article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes …

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The Prevention Of Preterm Labour – Corticotropin Releasing Hormone Type 1 Receptors As A Target For Drug Design And Development, Paul A. Keller, K. Kirkwood, J. Morgan, S. Westcott, A. Mccluskey

Paul Keller

The role of the corticotropin releasing hormone in the onset of labour and the subsequent medicinal chemistry implications of CRH antagonists for the prevention of premature birth, and identification of the CRH type 1 receptor as the target for this drug design, are reviewed here.

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A New Methodology For The Simulation Of Flexible Protein – Ligand Interactions, James A. Garner, John Deadman, David I. Rhodes, Renate Griffith, Paul A. Keller

Paul Keller

A methodology has been developed for the simulation of induced fit between a ligand and its target protein. It utilizes constrained molecular dynamics where atoms determined to be immobile from difference distance matrix studies are fixed. Application of this methodology to HIV-1 reverse transcriptase (RT) as the example target protein has demonstrated its robustness. Short simulation times are sufficient to achieve good refinement of docking poses resulting from exchange of structurally dissimilar inhibitors between crystal structures.

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Corticotropin Releasing Hormone - A Gpcr Drug Target, C. Hemley, A. Mccluskey, Paul A. Keller

Paul Keller

Corticotrophin Releasing Hormone (CRH) is a primary hormone in the fight or flight response targeting a membrane bound G-protein coupled receptor (GPCR). Many people worldwide stand to benefit by the development of CRH agonists and antagonists for the treatment of anxiety and depression, with additional therapeutic targets including Alzheimer’s, pain and the prevention of premature birth: so why the delay in development? In this review, we will discuss not only CRH, related proteins, receptors and ligands, but some of the obstacles that have arisen, as well as strategies being pursued to overcome these problems in the pursuit of this GPCR …

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Combining Structure-Based Drug Design And Pharmacophores, Renate Griffith, T. T. T. Luu, James A. Garner, Paul A. Keller

Paul Keller

Development towards integrated computer-aided drug design methodologies is presented by utilising crystal structure complexes to produce structure-based pharmacophores. These novel pharmacophores represent the ligand features that are involved in interactions with the target protein, as well as the space around the ligand occupied by the protein. The protein-ligand complexes can also yield information about all interactions that ligands could potentially form with the binding site, as well as about the size of the binding cavity. Together, these describe a 'superligand', which can also be viewed as a pharmacophore. Various types of novel pharmacophores are discussed and compared, using HIV-1 Reverse …

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Full-Text Articles in Physical Sciences and Mathematics

Synthesis Of Reaction-Ready 6,6 '-Biindole And 6,6 '-Biisatin Via Palladium(Ii)-Catalysed Intramolecular C-H Functionalisation, Allan B. Gamble, Paul A. Keller

Paul Keller

The First Syntheses Of Enantiopure 2,2 '-Biindoline, Steven M. Wales, Anthony C. Willis, Paul A. Keller

Paul Keller

Reductive Ring Opening Reactions Of Diphenyldihydrofullerenylpyrroles, William Hawkins, Paul A. Keller, Stephen G. Pyne

Paul Keller

Revealing Indigenous Indonesian Traditional Medicine: Anti-Infective Agents, Paul A. Keller, Ari Satia Nugraha

Paul Keller

Binaphthyl-Anchored Antibacterial Tripeptide Derivatives With Hydrophobic C-Terminal Amino Acid Variations, John Bremner, Paul A. Keller, Stephen Pyne, Mark Robertson, Kandasamy Sakthivel, Kittiya Somphol, Dean Baylis, Jonathon A Coates, John Deadman, Dharshini Jeevarajah, David I. Rhodes

Paul Keller

Synthesis Of Novel N-Protected Hydrophobic Phenylalanines And Their Application In Potential Antibacterials, Timothy P. Boyle, J. B. Bremner, Jonathan A. Coates, John Deadman, Paul A. Keller, Stephen G. Pyne, Kittiya Somphol

Paul Keller

Phytochemical And Biological Activity Studies Of The Bhutanese Medicinal Plant Corydalis Crispa, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Thanapat Sastraruji, Malai Taweechotipatr, Roonglawan Rattanajak, Aunchalee Tonsomboon, Sumalee Kamchonwongpaisan

Paul Keller

Antimalarial Alkaloids From A Bhutanese Traditional Medicinal Plant Corydalis Dubia, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Anthony C. Willis, Sumalee Kamchonwongpaisan

Paul Keller

Structural Re-Assignment Of The Mono- And Bis-Addition Products From The Addition Reactions Of N-(Diphenylmethylene)Glycinate Esters To [60]Fullerene Under Bingel Conditions, Graham E Ball, Glenn Ashley Burley, Leila Chaker, William Hawkins, James Williams, Paul A. Keller, Stephen G. Pyne

Paul Keller

Synthesis And In Vitro Binding Of N,N-Dialkyl-2-Phenylindol-3-Ylglyoxylamides For The Peripheral Benzodiazepine Binding Sites, T. P. Homes, F. Mattner, Paul A. Keller, A. Katsifis

Paul Keller

Synthesis Of Some Cyclic Indolic Peptoids As Potential Antibacterials, Vicki S. Au, John B. Bremner, Jonathan Coates, Paul A. Keller, Stephen G. Pyne

Paul Keller

[60]Fullerene Amino Acids And Related Derivatives, Glenn A. Burley, Paul A. Keller, Stephen G. Pyne

Paul Keller

Reactions Of Iminoglycines With C60 Fullerene And Their Unambiguous Characterisation Using Nmr Spectroscopy, Paul A. Keller, Stephen G. Pyne, Bill C. Hawkins

Paul Keller

New Cyclic Peptides Via Ring-Closing Metathesis Reactions And Their Anti-Bacterial Activities, Timothy P. Boyle, John B. Bremner, Jonathan Coates, John Deadman, Paul A. Keller, Stephen G. Pyne, David I. Rhodes

Paul Keller

Regioselective Synthesis Of Novel E-Edge-[60]Fullerenylmethanodihydropyrroles And 1,2-Dihydromethano[60]Fullerenes, Leila Chaker, Graham E. Ball, James R. Williams, Glenn A. Burley, Bill C. Hawkins, Paul A. Keller, Stephen G. Pyne

Paul Keller

The Role Of The Hpa Axis In Psychiatric Disorders And Crf Antagonists As Potential Treatments, Paul A. Keller, A. Mccluskey, J. Morgan, S. M. O'Connor

Paul Keller

A Convenient And Efficient Synthesis Of (S)-Lysine And (S)-Arginine Homologues Via Olefin Cross-Metathesis, Timothy P. Boyle, John B. Bremner, Jonathan A. Coates, Paul A. Keller, Stephen G. Pyne

Paul Keller

Antimalarial Activity Of 2,4-Diaminopyrimidines, J. Morgan, R. Haritakul, Paul A. Keller

Paul Keller

Aryl Nitro Reduction With Iron Powder Or Stannous Chloride Under Ultrasonic Irradiation, A. B. Gamble, James A. Garner, Christopher Gordon, S. M. J. O'Conner, Paul A. Keller

Paul Keller

Control Of Hiv Through The Inhibition Of Hiv-1 Integrase: A Medicinal Chemistry Perspective, Christopher Gordon, R. Griffith, Paul A. Keller

Paul Keller

The Prevention Of Preterm Labour – Corticotropin Releasing Hormone Type 1 Receptors As A Target For Drug Design And Development, Paul A. Keller, K. Kirkwood, J. Morgan, S. Westcott, A. Mccluskey

Paul Keller

A New Methodology For The Simulation Of Flexible Protein – Ligand Interactions, James A. Garner, John Deadman, David I. Rhodes, Renate Griffith, Paul A. Keller

Paul Keller

Corticotropin Releasing Hormone - A Gpcr Drug Target, C. Hemley, A. Mccluskey, Paul A. Keller

Paul Keller

Combining Structure-Based Drug Design And Pharmacophores, Renate Griffith, T. T. T. Luu, James A. Garner, Paul A. Keller

Paul Keller