• Emulsifying Properties of an Homologous Series of Medium- and Long-Chain d-Maltotriose Esters and their Impacts on the Viabilities of Selected Cell Lines

    The development of functional as well as nutritional surfactants for the food industry remains a matter of great interest. In the present study, a series of 6″-O-acylmaltotriose monoesters bearing alkyl side chains of 10–18 carbons was prepared by enzymatic means. The emulsions derived from those monoesters incorporating palmitoyl, stearoyl, and oleoyl side chains generally displayed advantageous shelf-lives, superior resistance to environmental variations, and more favorable droplet size distributions as well as stronger cytotoxic effects against various cancer cell lines. Ester 6 was shown to significantly inhibit the proliferation of MCF-7 breast cancer cells by inducing G1 phase arrest. Specifically, the levels of the G1 phase-related markers cyclin D1 and cyclin E as well as the cycle-dependent kinase 4 were suppressed by this particular ester. This study thus reveals that maltotriose esters can not only serve as novel functional food emulsifiers but also act, in vitro, as notable cytotoxic agents through a well-defined mechanism-of-action.

  • Synthesis of Functionally and Stereochemically Diverse Polymers via Ring-Opening Metathesis Polymerization of Derivatives of the Biomass-Derived Platform Molecule Levoglucosenone Produced at Industrial Scale

    The commercially available, abundant and homochiral cellulose pyrolysis product levoglucosenone (LGO) together with the readily derived isolevoglucosenone (isoLGO) form, in a stereoselective manner, Diels−Alder adducts with cyclopentadiene (CPD). These ring-fused norbornene systems, each of which incorporates six centers of chirality and is pseudoenantiomeric in nature, undergo ring-opening metathesis polymerization (ROMP) in the presence of a range of ruthenium-based catalysts to produce polymers embodying both carbo- and heterocyclic motifs. Under such conditions, controlled polymerizations take place with target molecular weights matching the theoretical ones and with low dispersities (from 1.1 to 1.4) normally being observed. Reduction of the carbonyl group in the Diels−Alder adduct derived from LGO provides the corresponding epimeric alcohols that can be etherified and the resulting ethers, including fluorine-containing ones, also yield well-controlled polymers via ROMP. This thus represents an efficient method for producing stereochemically and functionally diverse polymers from a renewable feedstock available at an industrial scale. These polymerizations are living ones as demonstrated by the facile preparation of block copolymers from the two Diels−Alder adducts.

  • Sucrose fatty acid esters: synthesis, emulsifying capacities, biological activities and structureproperty profiles

    The notable physical and chemical properties of sucrose fatty acid esters have prompted their use in the chemical industry, especially as surfactants, since 1939. Recently, their now well-recognized value as nutraceuticals and as additives in cosmetics has significantly increased demand for ready access to them. As such a lecture of current methods for the preparation of sucrose fatty acid esters by both chemical and enzymatic means is warranted and is presented here together with an account of the historical development of these compounds as surfactants (emulsifiers). The somewhat belated recognition of the antimicrobial, anticancer and insecticidal activities of sucrose esters is also discussed along with a commentary on their structure-property profiles.

  • Structural Modifications of a Flaxseed Lignan in Pursuit of Higher Liposolubility: Evaluation of the Antioxidant and Permeability Properties of the Resulting Derivatives

    While lignans and their biogenetic precursors can have various health benefits, the poor liposolubilities of such phenolic systems have restricted their application as antioxidants in the food industry. The research reported here was aimed at addressing these matters through derivatizing certain forms of such compounds and then assessing their properties as potential nutraceuticals. In particular, crude flaxseed lignan was purified to afford secoisolariciresinol diglucoside (SDG, 1) that was then subjected to structural modification. By such means, the SDG long-chain fatty acid esters 4−9 and 11−13, the fully acetylated SDG 10, secoisolariciresinol (SECO, 2), and anhydrosecoisolariciresinol (ASECO, 14) were obtained. The antioxidant activities of these derivatives were determined while their permeability properties were evaluated. Such studies revealed that certain SDG derivatives possessing useful liposolubilities also retained their antioxidative properties, as well as being capable of permeating Caco-2 cell monolayers while being nontoxic to them. SDG fatty acid esters 4−9 and 11−13 could be developed into emulsifiers with enhanced health benefits, especially considering their improved antioxidative (ca. <11 000 μmol Trolox/g) and permeability properties. This study thus highlights strategies for the structural modification of SDG so as to generate derivatives with superior properties in terms of their utility in the food and pharmaceutical industries.

  • The Synthesis of Certain Phomentrioloxin A Analogues and Their Evaluation as Herbicidal Agents

     A series of 28 analogues of the phytotoxic geranylcyclohexentriol (−)-phomentrioloxin A (1) has been synthesized through cross-couplings of various enantiomerically pure haloconduritols or certain deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues display modest herbicidal activities, and physiological profiling studies suggest that analogue 4 inhibits photosystem II in isolated thylakoids in vitro. 

  • Phenotypic screening and chemical biology: successes, challenges and lessons learnt during the development of potent and selective inhibitors of cell death

    Screening of small molecule libraries directly on cells, a technique also called phenotypic screening, has experienced a renaissance in the last decade. Recent improvements in this approach have made it an extremely powerful method to discover new biology and new starting points for the development of first-in-class drugs.Phenotypic screening has several advantages: identification and selection of small molecules intrinsically more drug-like (because they are already active in a relevant cellular model) and displaying early evidence of on-target modulation of a therapeutically relevant biological pathway. However, phenotypic screening still presents many challenges including the requirement for extensive target deconvolution.This seminar will illustrate this approach in the context of cell death with the development of potent and selective inhibitors of BAK-mediated apoptosis and how these chemical probes have enabled new insights into the apoptotic pathway. Importantly, this work also opens many opportunities to validate the therapeutic use of inhibitors of apoptosis.A/Prof Guillaume Lessene trained as an organic chemist, completing his PhD at the University of Bordeaux, before undertaking postdoctoral work with Prof Feldman at the Pennsylvania State University. Since moving to WEHI in 2001, his major research focus has been the development of small molecules that target the apoptotic and necroptotic cell death pathways. Since January 2019, he heads the New Medicines and Advanced Technologies Theme at WEHI. This multidisciplinary Theme comprises basic research driven by structural and chemical biology, translation of basic discoveries into new medicines together with clinical research, and cutting-edge technologies. He has published over 53 peer reviewed articles in top journals such as Science, Nature, Nat. Commun., Nat. Chem. Biol., Blood, Leukemia and Angew. Chem. Int. Ed.

  • Developing Drugs Targeting Cell Death to Treat Cance

    Peter Czabotar, a structural biologist, obtained his PhD from Curtin University in Perth, Australia, followed by post-doctoral research at the National Institute for Medical Research in London, UK. He subsequently moved to WEHI to focus on cell death proteins and drug discovery and was part of the team that developed Venetoclax. Peter was co-awarded the Eureka Prize for Innovation in Medical Research in 2016 and the ATSE Clunies Ross Commercialisation Award in 2018. In 2015 he received the Gottschalk Medal, Awarded by the Australian Academy of Science, for his work on cell death proteins. He is currently joint head of the Structural Biology Division at the Walter and Eliza Hall Institute of Medical Research.