Papers by Andrea Robinson
Marine Drugs
Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, ... more Elevenins are peptides found in a range of organisms, including arthropods, annelids, nematodes, and molluscs. They consist of 17 to 19 amino acid residues with a single conserved disulfide bond. The subject of this study, elevenin-Vc1, was first identified in the venom of the cone snail Conus victoriae (Gen. Comp. Endocrinol. 2017, 244, 11–18). Although numerous elevenin sequences have been reported, their physiological function is unclear, and no structural information is available. Upon intracranial injection in mice, elevenin-Vc1 induced hyperactivity at doses of 5 or 10 nmol. The structure of elevenin-Vc1, determined using nuclear magnetic resonance spectroscopy, consists of a short helix and a bend region stabilised by the single disulfide bond. The elevenin-Vc1 structural fold is similar to that of α-conotoxins such as α-RgIA and α-ImI, which are also found in the venoms of cone snails and are antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). In ...
Enantioselective hydrogenation of a series of (E)-a-substituted b-amidoacrylates using Rh(I)-cata... more Enantioselective hydrogenation of a series of (E)-a-substituted b-amidoacrylates using Rh(I)-catalysts with chiral phosphine ligands (BPE, DuPHOS) gives b-amino acid derivatives with enantioselectivities of up to 67%. A b-amino acid derivative was also synthesised with similar enantioselectivity (665%) from the corresponding prochiral enamide. 2005 Elsevier Ltd. All rights reserved.
Toxins, 2020
Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modificatio... more Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets—nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the un...
The Journal of biological chemistry, Jan 27, 2018
The development of fast-acting and highly stable insulin analogues is challenging. Insulin underg... more The development of fast-acting and highly stable insulin analogues is challenging. Insulin undergoes structural transitions essential for binding and activation of the insulin receptor (IR), but these conformational changes can also affect insulin stability. Previously, we substituted the insulin A6-A11 cystine with a rigid, non-reducible C=C linkage ("dicarba" linkage). A -alkene permitted the conformational flexibility of the A-chain N-terminal helix necessary for high-affinity IR binding, resulting in surprisingly rapid activity Here, we show that, unlike the rapidly acting LysPro insulin analogue (KP insulin), -dicarba insulin is not inherently monomeric. We also show that -dicarba KP insulin lowers blood glucose levels even more rapidly than KP insulin, suggesting that an inability to oligomerize is not responsible for the observed rapid activity onset of -dicarba analogues. Although rapid-acting, neither dicarba species is stable, as assessed by fibrillation and ther...
Scientific reports, Jan 8, 2017
The structural transitions required for insulin to activate its receptor and initiate regulation ... more The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro. Further biophysical, crystallographic and molecular-dynamics analyses reveal that the A6-A11 bond configuration directly affects the conformational flexibility of insulin A-chain N-terminal helix, dictating insulin's ability to engage its receptor. We reveal that in native insulin, contraction of the Cα-Cα distance of the flexible A6-A11 cystine allows the A-chain N-terminal helix to unwind to a conformation that allows receptor engagement. This motion is...
Tetrahedron Letters, 2004
Dicarba cyclic peptide analogues of the cyclic peptide octreotide have been synthesised in good y... more Dicarba cyclic peptide analogues of the cyclic peptide octreotide have been synthesised in good yields using a single pot, on resin, tandem homogeneous metal-catalysed metathesis-hydrogenation sequence.
New Journal of Chemistry, 2003
Five-and six-membered cyclic amino acids can be prepared in good yield with high ee (> 95%) via t... more Five-and six-membered cyclic amino acids can be prepared in good yield with high ee (> 95%) via tandem rhodium-DuPHOS catalysed asymmetric hydrogenation followed by a rhodium-catalysed hydroformylationcyclisation sequence in a single pot. The synthesis can be achieved using Rh-DuPHOS as the sole catalyst.
The Journal of Organic Chemistry, 2001
The Journal of Organic Chemistry, 2001
Rh-DuPhos-catalyzed asymmetric hydrogenation of R,-diamidoacrylates provides a highly efficient a... more Rh-DuPhos-catalyzed asymmetric hydrogenation of R,-diamidoacrylates provides a highly efficient and enantioselective route to chiral R,-diaminopropanoic acid derivatives. The mechanistic course of the hydrogenation was studied using isotopically enriched enamide complexes and phosphorus and carbon NMR. Addition of methyl R-N-benzoyl-N-acetyl-diaminopropenoate to the solvated catalyst gave a single 1:1 enamide complex and demonstrated the binding of the olefin and R-amide carbonyl group; the carboxylate and-N-acyl groups did not bind to the metal. Changes to the electronic and steric properties of theN -acyl group were well tolerated; however, small changes to the binding R-N-acyl group were found to significantly affect hydrogenation yields.
Green Chem., 2006
Renewable natural oils can be converted into potentially high value terminal oxygenates by a sing... more Renewable natural oils can be converted into potentially high value terminal oxygenates by a single-pot, high yielding metathesis-isomerisation-methoxycarbonylation-transesterification reaction sequence.
Green Chemistry, 2006
High conversion and selectivity can be obtained for the cross-metathesis of 2-butene with triglyc... more High conversion and selectivity can be obtained for the cross-metathesis of 2-butene with triglycerides and unsaturated fatty acid esters derived from natural oils. This can be achieved with remarkably high productive catalyst turnovers using second-generation ruthenium-based olefin metathesis catalysts.
Green Chem., 2012
A quaternary ammonium Hoveyda-Grubbs olefin metathesis pre-catalyst has been reversibly immobiliz... more A quaternary ammonium Hoveyda-Grubbs olefin metathesis pre-catalyst has been reversibly immobilized on sulphonic acid-functionalised silica-coated iron oxide magnetic particles to affect ring closing metathesis with easy removal, reuse and regeneration.
Chemical Communications, 2005
The cross-metathesis of synthetic and natural triglycerides containing unsaturated fatty acids wi... more The cross-metathesis of synthetic and natural triglycerides containing unsaturated fatty acids with 2-butene can be achieved with high conversion and excellent productive turnovers. These reactions are catalysed by second-generation ruthenium-based olefin metathesis catalysts and can be conducted at 25 uC in liquid 2-butene. COMMUNICATION www.rsc.org/chemcomm | ChemComm
Australian Journal of Chemistry, 2011
Three new morphine-based compounds bearing arginyl moieties, compounds 7, 9a, and 9b, have been s... more Three new morphine-based compounds bearing arginyl moieties, compounds 7, 9a, and 9b, have been synthesized using solid phase and solution phase techniques with the aim of obtaining new transdermal analgesics. Preliminary biological assays have shown that these compounds have a relatively high affinity for opioid receptors, achieving ≥94 % inhibition of radioligand binding at a concentration of 10 µM in non-selective opioid binding assays. Further testing on two of the analogues, 9a and 9b, demonstrated that these compounds were acting as agonists, rather than antagonists, at the opioid receptors and 9b achieved the significant result of 73 % inhibition of contractile responses in the electrically stimulated guinea pig ileum assay at a concentration of 30 µM. Unfortunately, none of the molecules showed evidence of transdermal activity.
Journal of Peptide Science, 2013
Highly efficient synthesis of lipidic amino acids can be achieved via Ru‐alkylidene‐catalysed cro... more Highly efficient synthesis of lipidic amino acids can be achieved via Ru‐alkylidene‐catalysed cross metathesis of long chain alkenes with commercially available allylglycine. The resultant unsaturated analogues can be then optionally hydrogenated under mild reaction conditions by using the spent metathesis catalyst. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.
The Journal of Organic Chemistry, 2006
A method to facilitate regioselective formation of multiple dicarba isosteres of cystine is descr... more A method to facilitate regioselective formation of multiple dicarba isosteres of cystine is described. A sequence of ruthenium-catalyzed cross metathesis and rhodium-catalyzed hydrogenation of nonproteinaceous allylglycine derivatives has been developed to achieve high-yielding and unambiguous formation of diaminosuberic acid derivatives. Allylglycine derivatives readily undergo ruthenium-catalyzed metathesis and hydrogenation to yield diaminosuberic acid derivatives in near quantitative yield. Under the same experimental conditions, prenylglycine was found to be inert to both Grubbs' and Wilkinson's catalyzed metathesis and hydrogenation, respectively, but was readily activated for metathesis via cross metathesis with Z-butene. Subsequent cross metathesis of the metathesis-formed crotylglycine derivative, followed by hydrogenation, yielded the second diaminosuberic acid derivative in excellent yield.
Cardiovascular Engineering and Technology
PURPOSE Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of n... more PURPOSE Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class. METHODS In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model. RESULTS Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3. CONCLUSIONS Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies.
The invention relates to peptides comprising the carboxy terminal sequence of a growth hormone or... more The invention relates to peptides comprising the carboxy terminal sequence of a growth hormone or an analogue of such a peptide in which the disulfide bridge is replaced by a dicarba bridge. Compositions containing such dicarba bridged peptides and method of treating obesity in an animal such as a human comprising administration of such dicarba bridged peptides are also disclosed.
Tetrahedron, 2011
A set of heterocyclic ligands have been synthesised for use in the preparation of mixed mode affi... more A set of heterocyclic ligands have been synthesised for use in the preparation of mixed mode affinity chromatographic adsorbents for application in the purification of proteins, including antibodies. The ligand structures were designed to consist of a pyridinyl or related aza-heterocyclic nucleus bearing a pendant arm containing either an alkylamine, alkylthiol or hydroxyalkyl nucleophilic group to allow their facile immobilisation onto an activated support matrix. Ligand diversity was achieved by altering the length of the alkyl chain between the heterocyclic nucleus and nucleophilic group, varying the position of alkyl chain attachment to the heterocycle, and incorporating extra substituents into the pyridinyl or related aza-heterocyclic ring. This diversity in ligand structure was intended to enable key structural features of the ligand, required for efficient protein binding, to be determined. In contrast to the previously used multi-step procedures for the preparation of analogous substituted pyridine or azaheterocyclic compounds, the synthesis routes for the ligands described here have generally utilized very mild, one-step reactions with readily available heterocyclic precursors.
Synthesis, 2013
A concise synthesis of spiropyrrolidines and spiropiperidines has been developed. The approach em... more A concise synthesis of spiropyrrolidines and spiropiperidines has been developed. The approach employs a rutheniumalkylidene-catalysed cross-metathesis reaction of enantiopure Nprotected allylglycine with methylenecycloalkanes. The resultant alkene intermediates can then undergo a tandem acid-catalysed cyclisation to form spiropyrrolidines. Ring expansion of the spiropyrrolidine system, via an aziridinium intermediate, grants access to the homologous spiropiperidine ring system with excellent stereoretention.
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Papers by Andrea Robinson