The University of Western Australia
Dr Scott Stewart
Lecturer
Contact details
| Address | Chemistry The University of Western Australia (M313) 35 Stirling Highway CRAWLEY WA 6009 Australia |
|---|---|
| Phone | 6488 3180 |
| Fax | 6488 1005 |
| scott.stewart@uwa.edu.au |
Location
Room 330, Molecular and Chemical Sciences Building, Crawley campus
Biography
Dr Scott Stewart completed a PhD at the Research School of Chemistry (ANU) on the enantioselective synthesis of two new anti-cancer agents Taxol and Phomopsidin under the supervision of Prof M Banwell. In 2002, Dr Stewart was awarded with an Alexander Humboldt Fellowship to work in the Tietze laboratories at the Universität Göttingen, Germany, on palladium mediated transformations in natural product synthesis. He has had additional, research stays with Prof P Scammells (Monash University) and A/Prof A McCluskey (Newcastle University) before being appointed at The University of Western Australia in late 2005.
Key research
- Research interests include the synthesis of biologically active natural products utilising the palladium catalysed cross coupling reaction as a key step transformation. The group is also involved in using domino transformations (a process in which two or more bond forming reactions are carried out such that the latter reaction is facilitated by functional groups created by the first) in synthetic chemistry en route to novel and interesting organic compounds. Medicinal chemistry interests include the synthesis of libraries of small molecules for the treatment of cancer and immune diseases. Recently, a series of new thalidomide analogues have been produced for the inhibition of tumour necrosis factor (TNF) expression. Methodological studies involving the improvement of the inter and intramolecular Heck reaction through the synthesis of new nickel (0) and palladium(0) catalysts are currently being explored.
Major research interests
- Synthetic organic chemistry
- Natural products and natural product synthesis
- Palladium and nickel mediated cross coupling reactions
- Domino transformations
- Medicinal chemistry
- Thalidomide
Qualifications
BSc Deakin, PhD A.N.U.
Publications
1. M. G. Banwell, B. L. Flynn, S. G. Stewart, Selective Cleavage of Isopropyl Aryl Ethers by Aluminium Trichloride, J. Org. Chem. 1998, 63, 9139.
2. D. M. J. Wright, S. P. Baker, S. G. Stewart, P. J. Scammells, N6-(5,6-epoxynorbornyl)adenosine Analogs as A1 Adenosine Agonists, Bioorg. Med. Chem. Lett. 1998, 8, 3647.
3. M. G. Banwell, S. G. Stewart, Methyl 6-methoxy-1-oxoindan-4-carboxylate, Org. Prep. Proced. Int, 2001, 33, 177.
4. M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe, M. D. McLeod, K. J. McRae,
S. G. Stewart, M. Vögtle, Chemoenzymatic Methods for the Enantioselective Preparation of Sesquiterpenoid Natural Products from Aromatic Precursors, Pure Appl. Chem, 2003, 75, 223.
5. M. G. Banwell, A. J. Edwards, M. D. McLeod, S. G. Stewart, A Chemoenzymatic Synthesis of the cis-Decalin Core Associated with the Novel Anti-Mitotic Agent Phomopsidin, Aust. J. Chem, 2004, 57,641.
6. L. F. Tietze, S. G. Stewart, M. E. Polomska, A. Modi, A. Zeeck, Towards the Synthesis of the New Anticancer Agent Mensacarcin, Chem, Eur. J. 2004, 10, 5233. [Impact Factor 5.3, citations 7].
7. L. F. Tietze, S. G. Stewart, M. E. Polomska, Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin, Eur. J. Org. Chem. 2005, 1752.
8. A. McCluskey, S. K. Leitch, J. Garner, C. E. Caden, T. A. Hill, L. R. Odell, S. G. Stewart, BiCl3-mediated opening of epoxides, a facile route to chlorohydrins or amino alcohols, Tetrahedron Lett. 2005, 46, 8229.
9. S. G. Stewart, M. E. Polomska, R. W. Lim, A concise synthesis of maleic anhydride and maleimide natural products found in Antrodia camphorata, Tetrahedron Lett. 2007, 48, 2241.
10. T. A. Hill, S. G. Stewart, B. Sauer, J. Gilbert, S. P. Ackland, J. A. Sakoff, A. McCluskey, Heterocyclic substituted cantharidin and norcantharidin analogues-synthesis, protein phosphatase (1 and 2A) inhibition and anticancer activity, Bioorg. Med. Chem. Letts, 2007, 17, 3392.
11. T. A. Hill, S. G. Stewart, S. P. Ackland, J. Gilbert, B. Sauer, J. A. Sakoff, A. McCluskey, Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation. Bioorg. Med. Chem. 2007, 15, 6126.
12. S. G. Stewart, D. Spagnolo, M. E. Polomska, M. Sin, M. Karimi, L. J. Abraham, Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling. Bioorg. Med. Chem Letts. 2007, 17, 5819.
13. S. G. Stewart, T. A. Hill, J. Gilbert, S. P. Ackland, J. A. Sakoff, A. McCluskey, Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity. Bioorg. Med. Chem. 2007, 15, 7301.
14. W. M. Loke, J. M. Proudfoot, S. Stewart, A. J. McKinley, P. W. Needs, P. A. Kroon, J. M. Hodgson and K. D. Croft, Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity, Biochemical Pharmacology, 2008, 75, 1045.
15. T. A. Hill, S. G. Stewart, C. P. Gordon, S. P. Ackland, J. Gilbert, B. Sauer, J. A Sakoff, A. McCluskey, Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition. ChemMedChem, 2008, 3, 1878.
16. S. G. Stewart, C. H. Heath, E. L. Ghisalberti, Domino or Single-Step Tsuji–Trost/Heck Reactions and their Application in the Synthesis of 3-Benzazepines and Azepino[4,5-b]indole Ring Systems. Eur. J. Org. Chem, 2009, 1934.
17. S. G. Stewart, L. A. Ho, M. E. Polomska, A. T. Percival, G. C. T. Yeoh, The rapid evaluation of Antrodia camphorata natural products and derivatives in tumorigenic liver progenitor cells using a novel cell proliferation assay. ChemMedChem, 2009, 4, 1657.
2. D. M. J. Wright, S. P. Baker, S. G. Stewart, P. J. Scammells, N6-(5,6-epoxynorbornyl)adenosine Analogs as A1 Adenosine Agonists, Bioorg. Med. Chem. Lett. 1998, 8, 3647.
3. M. G. Banwell, S. G. Stewart, Methyl 6-methoxy-1-oxoindan-4-carboxylate, Org. Prep. Proced. Int, 2001, 33, 177.
4. M. G. Banwell, A. J. Edwards, G. J. Harfoot, K. A. Jolliffe, M. D. McLeod, K. J. McRae,
S. G. Stewart, M. Vögtle, Chemoenzymatic Methods for the Enantioselective Preparation of Sesquiterpenoid Natural Products from Aromatic Precursors, Pure Appl. Chem, 2003, 75, 223.
5. M. G. Banwell, A. J. Edwards, M. D. McLeod, S. G. Stewart, A Chemoenzymatic Synthesis of the cis-Decalin Core Associated with the Novel Anti-Mitotic Agent Phomopsidin, Aust. J. Chem, 2004, 57,641.
6. L. F. Tietze, S. G. Stewart, M. E. Polomska, A. Modi, A. Zeeck, Towards the Synthesis of the New Anticancer Agent Mensacarcin, Chem, Eur. J. 2004, 10, 5233. [Impact Factor 5.3, citations 7].
7. L. F. Tietze, S. G. Stewart, M. E. Polomska, Intramolecular Heck Reactions for the Synthesis of the Novel Antibiotic Mensacarcin, Eur. J. Org. Chem. 2005, 1752.
8. A. McCluskey, S. K. Leitch, J. Garner, C. E. Caden, T. A. Hill, L. R. Odell, S. G. Stewart, BiCl3-mediated opening of epoxides, a facile route to chlorohydrins or amino alcohols, Tetrahedron Lett. 2005, 46, 8229.
9. S. G. Stewart, M. E. Polomska, R. W. Lim, A concise synthesis of maleic anhydride and maleimide natural products found in Antrodia camphorata, Tetrahedron Lett. 2007, 48, 2241.
10. T. A. Hill, S. G. Stewart, B. Sauer, J. Gilbert, S. P. Ackland, J. A. Sakoff, A. McCluskey, Heterocyclic substituted cantharidin and norcantharidin analogues-synthesis, protein phosphatase (1 and 2A) inhibition and anticancer activity, Bioorg. Med. Chem. Letts, 2007, 17, 3392.
11. T. A. Hill, S. G. Stewart, S. P. Ackland, J. Gilbert, B. Sauer, J. A. Sakoff, A. McCluskey, Norcantharimides, synthesis and anticancer activity: Synthesis of new norcantharidin analogues and their anticancer evaluation. Bioorg. Med. Chem. 2007, 15, 6126.
12. S. G. Stewart, D. Spagnolo, M. E. Polomska, M. Sin, M. Karimi, L. J. Abraham, Synthesis and TNF expression inhibitory properties of new thalidomide analogues derived via Heck cross coupling. Bioorg. Med. Chem Letts. 2007, 17, 5819.
13. S. G. Stewart, T. A. Hill, J. Gilbert, S. P. Ackland, J. A. Sakoff, A. McCluskey, Synthesis and biological evaluation of norcantharidin analogues: Towards PP1 selectivity. Bioorg. Med. Chem. 2007, 15, 7301.
14. W. M. Loke, J. M. Proudfoot, S. Stewart, A. J. McKinley, P. W. Needs, P. A. Kroon, J. M. Hodgson and K. D. Croft, Metabolic transformation has a profound effect on anti-inflammatory activity of flavonoids such as quercetin: Lack of association between antioxidant and lipoxygenase inhibitory activity, Biochemical Pharmacology, 2008, 75, 1045.
15. T. A. Hill, S. G. Stewart, C. P. Gordon, S. P. Ackland, J. Gilbert, B. Sauer, J. A Sakoff, A. McCluskey, Norcantharidin Analogues: Synthesis, Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition. ChemMedChem, 2008, 3, 1878.
16. S. G. Stewart, C. H. Heath, E. L. Ghisalberti, Domino or Single-Step Tsuji–Trost/Heck Reactions and their Application in the Synthesis of 3-Benzazepines and Azepino[4,5-b]indole Ring Systems. Eur. J. Org. Chem, 2009, 1934.
17. S. G. Stewart, L. A. Ho, M. E. Polomska, A. T. Percival, G. C. T. Yeoh, The rapid evaluation of Antrodia camphorata natural products and derivatives in tumorigenic liver progenitor cells using a novel cell proliferation assay. ChemMedChem, 2009, 4, 1657.
Funding received
Cancer Council of Western Australia
Ada Bartholomew Medical Research Trust Grant
School of Medicine, Dentistry and Health
UWA Priming Grant
NH&MRC
Ada Bartholomew Medical Research Trust Grant
School of Medicine, Dentistry and Health
UWA Priming Grant
NH&MRC
Memberships
2007-2008 Royal Australian Chemistry Institute Western Australian Committee Member
2004-2008 Australian Alexander Von Humboldt Society
2005-2008 Royal Australian Chemistry Institute Member
2006-2008 Exam and course reviewer for Taylors Teaching College
2004-2008 Australian Alexander Von Humboldt Society
2005-2008 Royal Australian Chemistry Institute Member
2006-2008 Exam and course reviewer for Taylors Teaching College
Teaching
CHEM3306 Modern Organic Synthesis (Course Coordinator)
CHEM3305 Biological Chemistry (Course Coordinator)
CHEM1102 Organic Chemistry (Course Coordinator)
CHEM3305 Biological Chemistry (Course Coordinator)
CHEM1102 Organic Chemistry (Course Coordinator)
Current projects
Small Alkyne Fungal Metabolite Synthesis (with A, Prof. E. Ghisalberti and L. Ho)
Alkyne 1, recently isolated by the Ghisalberti group, has been found to exhibit both anti fungal and plant growth activity qualities. The natural compound 1 was isolated as a metabolite produced by a fungus (SDEF 678) existing in the roots of Australian native grass Neurachne alopecurodea. This project focuses on an enantioselective synthesis of compound 1 from commercially available starting materials. Precursors formed in the process of this synthetic approach are to be assayed at for their anti-fungal properties and plant growth activity to determine which functional groups are essential in each process.
Pyrrolesesquiterpene Natural Product Synthesis (with Dr. M. Polomska)
Pyrrolosesquiterpene 2 has recently been isolated from a Streptomyces sp. (NPSOO8187) found in marine sediment collected in Alaska. This compound belongs to a pyrrole family of compounds which in the past have drawn much attention due to their biological activity and unique structure. The synthetic approach will focus on attaching a pyrrole ring precursors to enantiopure alkene diols. The latter compounds are anticipated to be synthesised from another natural product, geraniol. This project will investigate the synthesis of 2 as well as similar natural products isolated from the same species.
Synthesis of Thalidomide Derivatives (with A, Prof L. Abraham and C. Braun)
Since its discovery, thalidomide [(R,S)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione (R,S)-3 has had a tumultuous history as a medicinal agent. Administered in the 1950’s as a treatment for insomnia and as an antiemetic agent, the racemic compound (R,S)-3 was assumed to be non-toxic. Later investigations found that while the R-isomer (R)-3 was responsible for the sedative effect the S-isomer (S)-3 had teratogenic properties (causing foetus deformities). As a result, in 1962 this popular drug (R,S)-3, as prescribed for morning sickness, was withdrawn.
Currently, thalidomide (R,S)-3 use is undergoing a resurgence in the medical world. Attention has been focused on a widespread application in the research for treatment of various types of cancer including, multiple myeloma (MM), an as yet incurable form of bone marrow cancer. It is the aim of this project, through the invention of new synthetic pathways, is to provide more active analogues of thalidomide in the inhibition of tumour necrosis factor (TNF) expression. A library of new thalidomide compounds has been synthesised within the group varying at positions C4 and C5 (see compound 4). Several of these novel compounds have shown far greater inhibition of TNF transcription than thalidomide itself.
Natural Product Synthesis Utilising Palladium Catalysed Key Transformations (with C. Heath)
Synthetic transformations involving carbon-carbon bond formation catalysed by palladium species have been utilised in organic chemistry for many years. In particular, the Heck reaction (the coupling of an alkenyl or aryl halide species with an alkene) has found many uses in the synthesis of natural products because of its high turnover and excellent functional group compatibility. Synthetic projects are available targeting naturally occurring and medicinally important compounds in particular the preparation of newly discovered indole alkaloids. The yohimbine alkaloid skeleton within 5 (Class-1 alkaloids) containing a pentacyclic ring framework is one such entity. This compound, isolated from the bark of the Mitragyna africanus, is of particular interest as the plant itself is used for the treatment of mental disorders, bacterial infection and epilepsy. A project investigating the initial C-Ring formation via intramolecular Heck cyclisation and subsequent domino transformations are currently being carried out to target this natural product (5). Similarly, a synthesis of the (6-5-7) carbocyclic core contained within the natural product arboflorine (6) through domino Tsuji-Trost and Heck type transformations is also being investigated.
Synthesis of Maleic Anhydride and Maleimide Natural Products Found in Antrodia camphorata (with Prof. G. Yeoh, Dr. M. Polomska and L. Ho)
Antrodia camphorata is a parasitic fungus which grows on the inner heartwood of the native and endangered Taiwanese tree Cinnamomun kanehirai. This highly sought after fungus is used in traditional Chinese tribal medicine for the treatment of hypertension, liver cancer, drug intoxication and inflammation and can retail at c.a. AUD 19,000 per kg. Previous studies indicate that the Antrodia camphorata mycelium extract consists of many compounds including a new class of compounds bearing either a maleic anhydride 7 or a maleimide (8 and 9) carbocyclic core. Recently, within the group, a short synthesis of these three natural products has been devised using Negishi and Suzuki cross coupling methodology from chloro anhydride 10. Libraries of these compounds are currently being produced to compile a structure activity relationship (SAR) for their ability to inhibit the growth of liver cells and liver cancer cells.
Collaborators
A/Professor Lawrie Abraham, Biochemistry and Molecular Biology, UWA
Professor George Yeoh, Biochemistry and Molecular Biology, UWA
Professor Lutz F Tietze, Universität Göttingen
Frederick Pfeffer, School of Biological and Chemical Sciences, Deakin University
Alkyne 1, recently isolated by the Ghisalberti group, has been found to exhibit both anti fungal and plant growth activity qualities. The natural compound 1 was isolated as a metabolite produced by a fungus (SDEF 678) existing in the roots of Australian native grass Neurachne alopecurodea. This project focuses on an enantioselective synthesis of compound 1 from commercially available starting materials. Precursors formed in the process of this synthetic approach are to be assayed at for their anti-fungal properties and plant growth activity to determine which functional groups are essential in each process.
Pyrrolesesquiterpene Natural Product Synthesis (with Dr. M. Polomska)
Pyrrolosesquiterpene 2 has recently been isolated from a Streptomyces sp. (NPSOO8187) found in marine sediment collected in Alaska. This compound belongs to a pyrrole family of compounds which in the past have drawn much attention due to their biological activity and unique structure. The synthetic approach will focus on attaching a pyrrole ring precursors to enantiopure alkene diols. The latter compounds are anticipated to be synthesised from another natural product, geraniol. This project will investigate the synthesis of 2 as well as similar natural products isolated from the same species.
Synthesis of Thalidomide Derivatives (with A, Prof L. Abraham and C. Braun)
Since its discovery, thalidomide [(R,S)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione (R,S)-3 has had a tumultuous history as a medicinal agent. Administered in the 1950’s as a treatment for insomnia and as an antiemetic agent, the racemic compound (R,S)-3 was assumed to be non-toxic. Later investigations found that while the R-isomer (R)-3 was responsible for the sedative effect the S-isomer (S)-3 had teratogenic properties (causing foetus deformities). As a result, in 1962 this popular drug (R,S)-3, as prescribed for morning sickness, was withdrawn.
Currently, thalidomide (R,S)-3 use is undergoing a resurgence in the medical world. Attention has been focused on a widespread application in the research for treatment of various types of cancer including, multiple myeloma (MM), an as yet incurable form of bone marrow cancer. It is the aim of this project, through the invention of new synthetic pathways, is to provide more active analogues of thalidomide in the inhibition of tumour necrosis factor (TNF) expression. A library of new thalidomide compounds has been synthesised within the group varying at positions C4 and C5 (see compound 4). Several of these novel compounds have shown far greater inhibition of TNF transcription than thalidomide itself.
Natural Product Synthesis Utilising Palladium Catalysed Key Transformations (with C. Heath)
Synthetic transformations involving carbon-carbon bond formation catalysed by palladium species have been utilised in organic chemistry for many years. In particular, the Heck reaction (the coupling of an alkenyl or aryl halide species with an alkene) has found many uses in the synthesis of natural products because of its high turnover and excellent functional group compatibility. Synthetic projects are available targeting naturally occurring and medicinally important compounds in particular the preparation of newly discovered indole alkaloids. The yohimbine alkaloid skeleton within 5 (Class-1 alkaloids) containing a pentacyclic ring framework is one such entity. This compound, isolated from the bark of the Mitragyna africanus, is of particular interest as the plant itself is used for the treatment of mental disorders, bacterial infection and epilepsy. A project investigating the initial C-Ring formation via intramolecular Heck cyclisation and subsequent domino transformations are currently being carried out to target this natural product (5). Similarly, a synthesis of the (6-5-7) carbocyclic core contained within the natural product arboflorine (6) through domino Tsuji-Trost and Heck type transformations is also being investigated.
Synthesis of Maleic Anhydride and Maleimide Natural Products Found in Antrodia camphorata (with Prof. G. Yeoh, Dr. M. Polomska and L. Ho)
Antrodia camphorata is a parasitic fungus which grows on the inner heartwood of the native and endangered Taiwanese tree Cinnamomun kanehirai. This highly sought after fungus is used in traditional Chinese tribal medicine for the treatment of hypertension, liver cancer, drug intoxication and inflammation and can retail at c.a. AUD 19,000 per kg. Previous studies indicate that the Antrodia camphorata mycelium extract consists of many compounds including a new class of compounds bearing either a maleic anhydride 7 or a maleimide (8 and 9) carbocyclic core. Recently, within the group, a short synthesis of these three natural products has been devised using Negishi and Suzuki cross coupling methodology from chloro anhydride 10. Libraries of these compounds are currently being produced to compile a structure activity relationship (SAR) for their ability to inhibit the growth of liver cells and liver cancer cells.
Collaborators
A/Professor Lawrie Abraham, Biochemistry and Molecular Biology, UWA
Professor George Yeoh, Biochemistry and Molecular Biology, UWA
Professor Lutz F Tietze, Universität Göttingen
Frederick Pfeffer, School of Biological and Chemical Sciences, Deakin University
Research profile
