Craig Hutton
University of Melbourne, School of Chemistry, Faculty Member
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Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that... more
Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed intere...
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Covalently cross-linked homodimeric Abeta peptides have been prepared by solid-phase peptide synthesis by exploiting... more
Covalently cross-linked homodimeric Abeta peptides have been prepared by solid-phase peptide synthesis by exploiting 'site-site interactions', and exhibit substantially increased oligomerisation and fibrillisation properties compared with the corresponding monomers.
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4-(Bromomethyl)-2-(methylthio)pyrimidine (26): yield 30%; an unstable oil; 'H NMR 6 2.62 (8, Me), 4.40 (8, CH2Br), 7.17 (d, J = 5 Hz, 5H), 8.68 (d, J = 5 Hz, 6-H); HRMS m/z (M+) calcd 217.9514, obsd 217.9521.... more
4-(Bromomethyl)-2-(methylthio)pyrimidine (26): yield 30%; an unstable oil; 'H NMR 6 2.62 (8, Me), 4.40 (8, CH2Br), 7.17 (d, J = 5 Hz, 5H), 8.68 (d, J = 5 Hz, 6-H); HRMS m/z (M+) calcd 217.9514, obsd 217.9521. 5-Bromo-4-(bromomethyl)-2-(methylthio)pyrimidine (27): yield ...
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Total synthesis of the highly functionalized cyclic peptide natural product, ustiloxin D, has been achieved in a convergent manner. Our strategy incorporates an asymmetric allylic alkylation to construct the tert-alkyl aryl ether linkage... more
Total synthesis of the highly functionalized cyclic peptide natural product, ustiloxin D, has been achieved in a convergent manner. Our strategy incorporates an asymmetric allylic alkylation to construct the tert-alkyl aryl ether linkage between the dopa and isoleucine residues. The elaborated β-hydroxydopa derivative is rapidly converted to a linear tripeptide through an ammonia-Ugi reaction. Subsequent cyclization and global deprotection affords ustiloxin D in six steps from a known β-hydroxydopa derivative.
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ABSTRACT The dopa–sulfinylnorvaline component of ustiloxins A and B has been prepared using an Evans salen–Al-catalysed aldol reaction with a 6-mercaptoisovanillin derivative, followed by incorporation of the norvaline group and... more
ABSTRACT The dopa–sulfinylnorvaline component of ustiloxins A and B has been prepared using an Evans salen–Al-catalysed aldol reaction with a 6-mercaptoisovanillin derivative, followed by incorporation of the norvaline group and asymmetric oxidation of the resulting sulfide to give the corresponding sulfoxide.
ABSTRACT The four stereoisomers of [3-2H1] phenylalanine have been prepared, each as a single enantiomer in ca. 98% diastereoisomeric excess and with ca. 99% deuterium incorporation, by side-chain bromination of phenylalanine derivatives,... more
ABSTRACT The four stereoisomers of [3-2H1] phenylalanine have been prepared, each as a single enantiomer in ca. 98% diastereoisomeric excess and with ca. 99% deuterium incorporation, by side-chain bromination of phenylalanine derivatives, followed by deuteriolysis of each of the diastereoisomeric product bromides with deuterium over 5% palladium-on-carbon. The latter reactions proceeded with retention of configuration. (2R, 3S)-[3-2H1]Phenylalanine reacted with (S)-phenylalanine ammonia-lyase to give [3-2H1]-trans-cinnamic acid, with 92% deuterium incorporation, while the (2R, 3R)-stereoisomer of the deuteriated phenylalanine gave [3-2H1]-trans-cinnamic acid with 27% deuterium incorporation. These results indicate that reaction of (R)-phenylalanine with the enzyme involves mainly loss of the 3-pro-R hydrogen and ammonia, in an antiperiplanar elimination process analogous to that previously reported for (S)-phenylalanine, while a minor pathway for reaction of (R)-phenylalanine is either isomerization to (S)-phenylalanine, before elimination, or snnperiplanar elimination.
... All rights reserved 00404020 94 700+000 00404020(94)E03592 Stereocontrolled Synthesis of Hydroxypheny1a1anine and Hydroxytyrosine Derivatives Christopher J. Easton, Craig A. Hutton, Peter D. Roselt and Edward RT ... Easton, CJ;... more
... All rights reserved 00404020 94 700+000 00404020(94)E03592 Stereocontrolled Synthesis of Hydroxypheny1a1anine and Hydroxytyrosine Derivatives Christopher J. Easton, Craig A. Hutton, Peter D. Roselt and Edward RT ... Easton, CJ; Hutton, CA; Rositano, G.; Tan, EWJ Org. ...
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ABSTRACT The stereoselectivity of the oxidation of 1,4-thiazane-3,5-dicarboxylate derivatives to the corresponding sulfoxides and sulfones was found to be dependent on the type of oxidant used and the conformational preference of the... more
ABSTRACT The stereoselectivity of the oxidation of 1,4-thiazane-3,5-dicarboxylate derivatives to the corresponding sulfoxides and sulfones was found to be dependent on the type of oxidant used and the conformational preference of the substrate. Direct oxidants, such as sodium periodate, peroxides and peracids, preferentially react with the axial sulfur lone-pair, providing the axial S-oxide. Oxidation with bromine–water yielded the epimeric equatorial S-oxide, presumably as a result of initial attack of the axial sulfur lone pair providing the axial bromosulfonium ion, with subsequent displacement of bromide by water leading to the equatorial S-oxide.
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Alzheimer&am... more
Alzheimer's disease (AD) is the most common age-related dementia. Unfortunately due to a lack of validated biomarkers definitive diagnosis relies on the histological demonstration of amyloid-beta (Abeta) plaques and tau neurofibrillary tangles. Abeta processing is implicated in AD progression and many therapeutic strategies target various aspects of this biology. While Abeta deposition is the most prominent feature of AD, oligomeric forms of Abeta have been implicated as the toxic species inducing the neuronal dysfunction. Currently there are no methods allowing routine monitoring of levels of such species in living populations. We have used surface enhanced laser desorption ionization time of flight (SELDI-TOF) mass spectrometry incorporating antibody capture to investigate whether the cellular membrane-containing fraction of blood provides a new source of biomarkers. There are significant differences in the mass spectra profiles of AD compared with HC subjects, with significantly higher levels of Abeta monomer and dimer in the blood of AD subjects. Furthermore, levels of these species correlated with clinical markers of AD including brain Abeta burden, cognitive impairment and brain atrophy. These results indicate that fundamental biochemical events relevant to AD can be monitored in blood, and that the species detected may be useful clinical biomarkers for AD.
Research Interests: Neuroscience, Brain, Humans, Female, Male, and 3 moreAged, Biological markers, and Alzheimer Disease
ABSTRACT The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The... more
ABSTRACT The preparation of tryptophan derivatives through the Lewis acid promoted substitution of aziridine carboxylates with indole was found to be accompanied by a ring-expansion reaction to generate an oxazolidinone byproduct. The ratio of tryptophan to oxazolidinone products can be optimized through a judicious choice of Lewis acid and N-protecting group.
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ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of extracellular amyloid plaques comprised from fibrillar aggregates of the amyloid-β peptide (Aβ). Cu2+ interactions with Aβ appear to be... more
ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of extracellular amyloid plaques comprised from fibrillar aggregates of the amyloid-β peptide (Aβ). Cu2+ interactions with Aβ appear to be involved in both the production of reactive oxygen species and the misfolding of Aβ into oligomeric intermediates including covalently cross-linked dimers. We have previously investigated the Cu2+ coordination of Aβ monomers in detail, whilst others have shown that Aβ fibrils coordinate Cu2+ in a similar manner to Aβ monomers. However, the coordination of low-molecular-weight Aβ species, which are believed to be responsible for neuronal dysfunction in AD, has not been widely investigated. Here, we report the first study of Cu2+ coordination by synthetic Aβ dimers containing an artificial diaminopimelic acid (DAP) or a dityrosine cross-link at residue 10. Our preliminary findings show that dityrosine cross-linking imparts unique structural constraints, resulting in Cu2+ coordination distinct from Aβ monomers and fibrils, which may be relevant to the greater toxicity of low-molecular-weight Aβ oligomers in AD.
The Ag(I)-promoted coupling of amino acids and peptides with amino ester thioamides generates peptide imides without epimerisation. The peptide imides undergo regioselective hydrolysis under mild conditions to generate native peptides.... more
The Ag(I)-promoted coupling of amino acids and peptides with amino ester thioamides generates peptide imides without epimerisation. The peptide imides undergo regioselective hydrolysis under mild conditions to generate native peptides. This method was employed to prepare the pentapeptide thymopentin in the N→C direction, in high yield and purity.
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ABSTRACT The 4-nitrophenyl ether is an efficient directing group in the asymmetric aminohydroxylation reaction of but-3-en-1-ol derivatives. Either regioisomeric product can be obtained with useful levels of enantioselectivity, allowing... more
ABSTRACT The 4-nitrophenyl ether is an efficient directing group in the asymmetric aminohydroxylation reaction of but-3-en-1-ol derivatives. Either regioisomeric product can be obtained with useful levels of enantioselectivity, allowing for the short enantioselective synthesis of GABOB and homoserine derivatives.
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ABSTRACT [formula: see text] Numerous biologically active cyclic peptides, such as the antibiotic vancomycin, contain amino acid residues connected through side-chain biaryl or aryl-alkyl ether linkages. Nucleophilic aromatic substitution... more
ABSTRACT [formula: see text] Numerous biologically active cyclic peptides, such as the antibiotic vancomycin, contain amino acid residues connected through side-chain biaryl or aryl-alkyl ether linkages. Nucleophilic aromatic substitution reactions have recently been shown to provide a general method for the formation of such ether linkages, and consequently the synthesis of functionalized fluoronitro-substituted aromatic amino acids is of great interest. Herein, a method for the stereospecific synthesis of 3-fluoro-4-nitro- and 4-fluoro-3-nitro-threo-beta-hydroxyphenylalanine is described.
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The polyhydroxylated beta-amino acids (2S,3R,4S,5S,7E)-3-amino-8-phenyl-2,4,5-trihydroxyoct-7-enoic acid (APTO) and (2S,3R,4S,5S,7E,9E)-3-amino-10-(4-ethoxyphenyl)-2,4,5-trihydroxydeca-7,9-dienoic acid (AETD) are key components of the... more
The polyhydroxylated beta-amino acids (2S,3R,4S,5S,7E)-3-amino-8-phenyl-2,4,5-trihydroxyoct-7-enoic acid (APTO) and (2S,3R,4S,5S,7E,9E)-3-amino-10-(4-ethoxyphenyl)-2,4,5-trihydroxydeca-7,9-dienoic acid (AETD) are key components of the microsclerodermin family of anti-fungal cyclic peptides. They have been synthesised in protected form in twelve steps using a unified strategy, with the introduction of the unsaturated sidechain in the final step of the synthesis from a common aldehyde intermediate. The synthesis features the ordered application of asymmetric aminohydroxylation and dihydroxylation reactions to efficiently introduce the stereochemistry of the targets with high selectivity.
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The dopa-sulfinylnorvaline component of ustiloxins A and B has been prepared using an Evans salen-Al-catalysed aldol reaction with a 6-mercaptoisovanillin derivative, followed by incorporation of the norvaline group and asymmetric... more
The dopa-sulfinylnorvaline component of ustiloxins A and B has been prepared using an Evans salen-Al-catalysed aldol reaction with a 6-mercaptoisovanillin derivative, followed by incorporation of the norvaline group and asymmetric oxidation of the resulting sulfide to give the corresponding sulfoxide.
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Association of proteins into homo- and hetero-oligomers plays an important role in a plethora of biological phenomena. Inhibition of these interactions is increasingly recognized as a valuable new direction in drug design. In this... more
Association of proteins into homo- and hetero-oligomers plays an important role in a plethora of biological phenomena. Inhibition of these interactions is increasingly recognized as a valuable new direction in drug design. In this mini-review we consider inhibition of protein misfolding and aggregation, molecules that disrupt enzyme quaternary structure, and signaling inhibitors, as emerging drugs.
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Bacterial biosynthesis of lysine has come under increased scrutiny as a target for novel antibacterial agents as it provides both lysine for protein synthesis and meso-diaminopimelate for construction of the bacterial peptidoglycan cell... more
Bacterial biosynthesis of lysine has come under increased scrutiny as a target for novel antibacterial agents as it provides both lysine for protein synthesis and meso-diaminopimelate for construction of the bacterial peptidoglycan cell wall. Recent studies of the enzymes of the lysine biosynthetic pathway, development of inhibitors and investigations of their antibacterial properties are discussed.
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4-(Bromomethyl)-2-(methylthio)pyrimidine (26): yield 30%; an unstable oil; 'H NMR 6 2.62 (8, Me), 4.40 (8, CH2Br), 7.17 (d, J = 5 Hz, 5H), 8.68 (d, J = 5 Hz, 6-H); HRMS m/z (M+) calcd 217.9514, obsd 217.9521.... more
4-(Bromomethyl)-2-(methylthio)pyrimidine (26): yield 30%; an unstable oil; 'H NMR 6 2.62 (8, Me), 4.40 (8, CH2Br), 7.17 (d, J = 5 Hz, 5H), 8.68 (d, J = 5 Hz, 6-H); HRMS m/z (M+) calcd 217.9514, obsd 217.9521. 5-Bromo-4-(bromomethyl)-2-(methylthio)pyrimidine (27): yield ...
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Covalently cross-linked homodimeric Abeta peptides have been prepared by solid-phase peptide synthesis by exploiting... more
Covalently cross-linked homodimeric Abeta peptides have been prepared by solid-phase peptide synthesis by exploiting 'site-site interactions', and exhibit substantially increased oligomerisation and fibrillisation properties compared with the corresponding monomers.
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The synthesis of the first members of a new class of cyclic peptide-containing hemicryptophanes is described. Synthesis was achieved through attachment of veratryl groups to the L-tyrosine side chains of a cyclic hexapeptide, c(YG)3,... more
The synthesis of the first members of a new class of cyclic peptide-containing hemicryptophanes is described. Synthesis was achieved through attachment of veratryl groups to the L-tyrosine side chains of a cyclic hexapeptide, c(YG)3, followed by intramolecular cyclodehydration to generate the CTV unit. The diastereomeric P- and M-hemicryptophanes were generated in a 2 : 1 ratio and were separated by chromatography. The enantioselective binding properties of the hemicryptophanes were investigated by complexation with carnitine. Both isomers were found to have significant selectivity for binding (R)-carnitine.