Arcanum of the exploded camera - Coley, Rob; Lockwood, Dean
‘A simple world corresponds to a simple animal’, said Von Uexküll. Of the oak tree, the ant perceives only the bark which is its hunting ground. What of photography in a War Universe? Like the ant, the photographer’s antennae twitch, sensing the image of horror like a thread of blood. Yes, the world is intolerable, but where is a critical horror adequate to the complexities of the 21st century?? Where is the paraphotography that will peel back the bark on Control’s vastations of the contemporary? This talk – through the prism of William Burroughs’ proposition that we live in a...
Diastereoselective additions of ethynyl Grignard reagent to erythrulose derivatives - Kobayashi, Shoji; Das, Parthasarathi; Wang, Guang Xing; Mita, Takashi; Lear, Martin J.; Hirama, Masahiro
Through systematic changes in reaction conditions and with the use of Ti(OiPr)4, the typical stereochemical outcome of
ethynylmagnesium bromide on α,β-O-isopropylidene-erythrulose derivatives has been reversed with exceptional levels of control.
Direct observation of ESR spectra of bicyclic nine-membered enediynes at ambient temperature - Hirama, Masahiro; Akiyama, Kimio; Das, Parthasarathi; Mita, Takashi; Lear, Martin J.; Iida, Kyo-ichiro; Sato, Itaru; Yoshimura, Fumihiko; Usuki, Toyonobu; Tero-Kubota, Shozo
The ESR spectra for synthetic bicyclo[7.3.0]epoxydodecadienediynes in solution at room temperature are steady. These spectra originate from the Masamune-Bergman cyclization of bicyclo[7.3.0]epoxydodecadienediynes to p-benzyne biradicals and the equilibrium between the two forms. Comparison of the ESR spectra of the unlabeled and 13C-labeled nine-membered enediynes indicated that the spectra are not directly due to the p-benzyne biradicals but rather to more stable secondary radical intermediates.
Laetirobin from the parasitic growth of Laetiporus sulphurous on Robinia pseudoacacia - Lear, Martin J.; Simon, Oliver; Foley, Timothy L.; Burkart, Michael D.; Baiga, Thomas J.; Noel, Joseph P.; DiPasquale, Antonio G.; Rheingold, Arnold L.; La Clair, James J.
Laetirobin (1) was isolated as a cytostatic lead from Laetiporus sulphureus growing parasitically on the black locust tree, Robinia pseudoacacia, by virtue of a reverse-immunoaffinity system. Using an LC/MS procedure, milligram quantities of laetirobin (1) were obtained, and the structure of 1 was elucidated by X-ray crystallography and confirmed by NMR spectroscopy. Preliminary cellular studies indicated that laetirobin (1) rapidly enters in tumor cells, blocks cell division at a late stage of mitosis, and invokes apoptosis.
Practical synthesis of maleimides and coumarin-linked probes for protein and antibody labelling via reduction of native disulfides - Song, Hong Y.; Ngai, Mun H.; Song, Zhen Y.; MacAry, Paul A.; Hobley, Jonathan; Lear, Martin J.
The cellular tracking, detection and sensing of protein or antibody movement are important aspects to advance our understanding of biomolecular interactions and activity. Antibodies modified with fluorescent dyes are also valuable tools, especially in immunology research. We describe here a proof-of-principle study of a new water-soluble coumarin probe with a maleimide thiol-reacting unit to fluorescently tag biomolecules. Highlights include: (1) a convenient water-based preparation of N-substituted maleimides, (2) a one-pot preparation of activated maleimido-esters, and (3) a bio-conjugation protocol for the selenol-promoted reduction of native disulfide bonds and the ‘site-specific’ labelling of antibodies with no significant loss of activity.
Virtual screening prediction of new potential organocatalysts for direct aldol reactions - Liu, Xiang Hui; Song, Hong Yan; Ma, Xiao Hua; Lear, Martin J.; Chen, Yu Zong
A support vector machine (SVM)-based virtual screening method is demonstrated as a rapid computational tool for the prediction of potential asymmetric organocatalysts for the direct aldol reaction. Our models show good accuracy at cross-validation and independent testing. Structure analyses of screening hits from the PubChem database revealed several new classes of compounds, including beta-amino acids, diamines and hydrazides, as potential chiral organocatalysts.
Total synthesis confirms laetirobin as a formal Diels-Alder adduct - Simon, Oliver; Reux, Bastien; La Clair, James J.; Lear, Martin J.
Laetirobin, isolated from a parasitic fungus host–plant relationship, was synthesized in six practical steps with an overall yield of 12% from commercially available 2,4-dihydroxyacetophenone. Because the product is a pseudosymmetric tetramer of benzo[b]furans, each step of the synthesis was designed to involve tandem operations. Highlights include: 1) the double Sonogashira reaction of a bis(alkyne), 2) the practical copper(I)-mediated formation of a bis(benzo[b]furan), and 3) the biomimetic [4+2] dimerization and unexpected cationic [5+2] annulation of gem-diaryl alkene precursors. Preliminary structure–activity relationship data between the isomeric [4+2] and [5+2] tetramers revealed only the natural product to possess promising anticancer potential. Specifically, laetirobin...
A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases - Ch'ng, J.-H.; Kotturi, S. R.; Chong, A. G.-L.; Lear, Martin J.; Tan, K. S.-W.
Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxytamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation....
Chemical modification and organelle-specific localization of orlistat-like natural-product-based probes - Yang, Peng-Yu; Liu, Kai; Zhang, Chongjing; Chen, Grace Y. J.; Shen, Yuan; Ngai, Mun Hong; Lear, Martin J.; Yao, Shao Q.
Orlistat, also known as tetrahydrolipstatin (THL), is an FDA-approved anti-obesity drug with potential anti-cancer activity. Previously, we developed a chemical proteomic approach, based on the Orlistat-like probe (1a) for large-scale identification of unknown cellular targets of Orlistat in human hepatocytes. In this article, we report the chemical synthesis and biological evaluation of an expanded set of Orlistat-like compounds, with the intention to further dissect and manipulate potential cellular targets of Orlistat. In doing so, we carried out proteome-wide activity-based profiling and large-scale pull-down/LCMS analysis of these compounds in live HepG2 cells, and successfully identified many putative cellular targets for Orlistat...
Parasite-based screening and proteome profiling reveal orlistat, an FDA-approved drug, as a potential anti trypanosoma brucei agent - Yang, Peng-Yu; Wang, Min; Liu, Kai; Ngai, Mun Hong; Sheriff, Omar; Lear, Martin J.; Sze, Siu Kwan; He, Cynthia Y.; Yao, Shao Q.
Trypanosoma brucei is a parasite that causes African sleeping sickness in humans and nagana in livestock and is transmitted by the tsetse fly. There is an urgent need for the development of new drugs against African trypanosomiasis due to the lack of vaccines and effective drugs. Orlistat (also called tetrahydrolipstatin or THL) is an FDA-approved antiobesity drug targeting primarily the pancreatic and gastric lipases within the gastrointestinal tract. It shows potential activities against tumors, mycobacteria, and parasites. Herein, we report the synthesis and evaluation of an expanded set of orlistat-like compounds, some of which showed highly potent trypanocidal activities in...
Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2 - Somanadhan, Brinda; Kotturi, Santosh R.; Yan Leong, Chung; Glover, Robert P.; Huang, Yicun; Flotow, Horst; Buss, Antony D.; Lear, Martin J.; Butler, Mark S.
A 384-well microtitre plate fluorescence cleavage assay was developed to identify inhibitors of the cysteine protease falcipain-2, an important antimalarial drug target. Bioassay-guided isolation of a MeOH extract from a mycobacterium Chitinophaga sp. Y23 isolated from soil collected in Singapore, led to the identification of a new acyltetrapeptide, falcitidin (1), which displayed an IC50 value of 6 mM against falcipain-2. The planar structure of 1 was secured by NMR and MS/MS analysis. Attempts to isolate further material for biological testing were hampered by inconsistent production and by a low yield (o100 mg l�1). The absolute configuration of 1 was determined...
A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria - Ch'ng, Jun-Hong; Mok, Sachel; Bozdech, Zbynek; Lear, Martin James; Boudhar, Aicha; Russell, Bruce; Nosten, Francois; Tan, Kevin Shyong-Wei
Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line
antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then,
resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the
efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/
chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to
CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to...
Remote 1,6-stereocontrol by iminium-mediated organocatalytic events - Lear, Martin J.; Hayashi, Yujiro
How can you catalyse the 1,6-conjugate addition of carbon-nucleophiles to acyclic, achiral 2,4-dienals enantioselectively? This question raises two key issues in catalysis: how to favour 1,6-regioisomers (over 1,4- or 1,2-adducts) and how to achieve a stereodifferentiating event at a weakly electrophilic site. While these issues are challenging enough, this very feat has been achieved by the Jørgensen group under remote iminium-stereocontrol, whereby δ-alkyl dienals can react with olefinic lactones in the presence of the Jørgensen-Hayashi catalyst to give 1,6-adducts exclusively.
Total synthesis of (−)-platensimycin by advancing oxocarbenium- and iminium-mediated catalytic methods - Eey, Stanley T.-C.; Lear, Martin J.
(-)-Platensimycin is a potent inhibitor of fatty acid synthase (FAS) that holds promise in the treatment of metabolic disorders (e.g., diabetes, “fatty liver”) and pathogenic infections (e.g., against drug-resistant bacteria). Herein, we describe its total synthesis through a four-step preparation of the aromatic amine fragment and an improved stereocontrolled assembly of the ketolide fragment, (-)-platensic acid. Key synthetic advances include: (i) a modified Lieben-haloform reaction to directly convert an aryl methyl ketone to its methyl ester within 30 seconds; (ii) an experimentally improved dialkylation protocol to platensic acid; (iii) a sterically-controlled chemo- and diastereoselective organocatalytic conjugate reduction of a spiro-cyclized...
Characterization of the commercially-available fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a marker for chloroquine resistance and uptake in a 96-well plate assay - Loh, Cheryl C. Y.; Suwanarusk, Rossarin; Lee, Yan Quan; Chan, Kitti W. K.; Choy, Kit-Ying; Rénia, Laurent; Russell, Bruce; Lear, Martin J.; Nosten, François H.; Tan, Kevin S. W.; Chow, Larry M. C.; Snounou, Georges
Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than...
Low temperature ignition of biomass - Jones, J. M.; Saddawi, A.; Dooley, B; Mitchell, E. J. S.; Werner, J.; Waldron, D. J.; Weatherstone, S.; Williams, A.
Abstract Biomass is an especially reactive fuel. There have been large increases in the transportation and utilization of biomass fuels over the past 10 years and this has raised concerns over its safe handling and utilization. Fires, and sometimes explosions, are a risk during all stages of fuel production as well as during the handling and utilization of the product. This paper presents a method for assessing ignition risk and provides a ranking of relative risk of ignition of biomass fuels. Tests involved single particle measurements, thermal analysis, dust layer and basket ignition tests. In all cases, smouldering combustion was observed,...
Effect of cognitive biases on human-robot interaction: a case study of robot's misattribution - Biswas, Mriganka; Murray, John
This paper presents a model for developing long-term human-robot interactions and social relationships based on the principle of 'human' cognitive biases applied to a robot. The aim of this work is to study how a robot influenced with human ‘misattribution’ helps to build better human-robot interactions than unbiased robots.
The results presented in this paper suggest that it is important to know the effect of cognitive biases in human characteristics and interactions in order to better understand how this plays a role in human-human social relationship development. The results presented in this paper show how a single cognitive memory bias i.e....
Reconstitution of membrane proteins: a GPCR as an example - Goddard, Alan; Dijkman, Patricia; Adamson, Roslin; Dos Reis, Rosana; Watts, Anthony
Membrane proteins are the gatekeepers to the cell and are essential to the function of all cells, controlling the flow of molecules and information across the cell membrane. Much effort has been put into the development of systems for studying membrane proteins in simplified environments that nevertheless mimic their native lipid environment. After isolation and production of purified membrane proteins in detergent, it is often necessary to reconstitute them into a lipid structure such as liposome, nanodisc, or lipodisq. Each of these has the advantage of returning the protein to a defined lipid environment, and the choice of system depends...