The University of Western Australia

Assoc/Prof Scott Stewart

Associate Professor
School of Chemistry and Biochemistry

Contact details

Address

School of Chemistry and Biochemistry
The University of Western Australia (M313)
35 Stirling Highway
CRAWLEY WA 6009
Australia

Phone

6488 3180

Fax

6488 1005

Email

scott.stewart@uwa.edu.au

Location

Room 330, Bayliss Building, Crawley campus

Qualifications

BSc Deakin, PhD ANU

Biography

A/Prof 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, A/Prof Stewart was awarded with an Alexander von-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. In 2010 A/Prof Stewart was awardedthe Athel Beckwith Lectureship for recently appointed organic chemistry lecturer’s along with a second Alexander von-Humboldt Fellowship.

Key research

Research interests include the synthesis of natural products and their simplified ring systems efficiently and mainly utilising the palladium catalysed cross coupling reaction as a key step transformation. The indole alkaloids Arboflorine, Ajmalicine and the Flinderoles are of interest particularly because of their novel molecular architecture and/or biological activity. Efficient synthesis of the Azepino[4,5-b]indoles and tetrahydro-β-carbolines are being perused within the group.

In the pursuit of efficient ring forming processes several domino type reactions have been devised by the group. “A domino reaction is a process involving two or more bond-forming reactions under identical conditions, in which the latter transformations take place at the functionalities obtained in the former-bond forming reactions” (Tietze). Domino reactions have the potential for saving time, resources, labour costs and separation aids. In the construction of the 3-benzazepines and Azepino[4,5-b]indole ring systems a domino Tsuji-Trost Heck reaction has been devised. Similarly, in conjunction with the Pfeffer Group (Deakin University) a domino Heck Aza-Michael reaction has been discovered in the formation of tetrahydro-β-carbolines.

A short synthesis of three maleimide natural products including Camphorataimide B has been devised within the group. These compounds isolated from 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. Several analogues of these simple molecular scaffolds have been prepared and

The group is also targeting the Pyrrolosesquiterpene and the as yet unnamed illustrated epoxiquinol. The former compound has recently been isolated from a Streptomyces sp. (NPSOO8187) found in marine sediment collected in Alaska. The epoxyquinole has recently isolated by the Ghisalberti group, has been found to exhibit both anti fungal and plant growth activity qualities.

Most recently, the synthetic methods in the preparation of indolizidine alkaloids and anthrapyranone natural products is being pursued. The indolizidine N-scaffold is found in natural products such as the Pumiliotoxins which are potential cardiotonic agents. The latter anthrapyranone natural products have been highlighted as highly active antimicrobial and anticancer agents which follow an interesting and not fully explored mode of action.

Medicinal chemistry pursuits include improving several key biological pathways of the infamous drug thalidomide [(R,S)-2-(2,6-Dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione (R,S). 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 was responsible for the sedative effect the S-isomer had teratogenic properties (causing foetus deformities). As a result, in 1962 this popular drug , as prescribed for morning sickness, was withdrawn. Currently, thalidomide (R,S) 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. Several of these novel compounds have shown far greater inhibition of TNF transcription than thalidomide itself. Recently the as yet unknown molecular mode of action of thalidomide is being perused with the formation of the first Biotin-Thalidomide analogue.

Publications

33. D. L. Priebbenow, S. G. Stewart, F. M. Pfeffer, Asymmetric Induction in Domino Heck-aza-Michael Reactions, Tetrahedron Lett. 2012, 53, accepted.

32. J. E. Rixson, T. Chaloner, C. H. Heath, L. F. Tietze, S. G. Stewart, The Development of Domino Reactions Incorporating the Heck Reaction: The Formation of N-Heterocycles, Eur. J. Org. Chem, 2012, 544-558.

31. M. Bradshaw, J. Zou, L. Byrne, K. S. Iyer, S. G. Stewart and Colin L. Raston, Pd(II) conjugated chitosan nanofibre mats for application in Heck cross-coupling reactions. Chem. Commun., 2011, 47, 12292-12294.

30. Y. S. Yee, Sven Kampmann, K. A. Stubbs, B. W. Skelton, B. J. Kaskow, L. J. Abraham, S. G. Stewart, Novel Thalidomide Analogues with Potent NFB and TNF expression Inhibition, Med. Chem. Commun., 2011, 2, 1073-1078.

29.R. E. Martin, M. E. Polomska, L. T. Byrne, S. G. Stewart An intramolecular Tsuji-Trost reaction based approach to the synthesis of 6-methylene indolizidines, Tetrahedron Lett. 2011, 52, 4878-4881.

28. D. L. Priebbenow, F. M. Pfeffer, S. G. Stewart, A One-Pot, Three-Component Approach to Functionalised Tetrahydroisoquinolines Using Domino Heck–aza-Michael Reactions, Eur. J. Org. Chem, 2011, 1632-1635.

27.J. Zou, K. S. Iyer, S. G. Stewart, C. L. Raston, A Scalable synthesis of catalysts for the Mizoroki–Heck cross coupling reaction: palladium nanoparticles assembled in a polymeric nanosphere. New J. Chem., 2011, 35, 854-860.

26. N. A. Lengkeek, R. A. Boulos, A. J. McKinley, T. V. Riley, B. Martinac, S. G. Stewart, The Synthesis of Fluorescent DNA The Synthesis of Fluorescent DNA Intercalator Precursors through Efficient Multiple Heck Reactions Aust J Chem, 2011, 64, 316-323.

25. D. L Priebbenow, S. G Stewart, F. M. Pfeffer, A General Approach to N-Heterocyclic Scaffolds Using Domino Heck-aza-Michael Reactions, Org. Biomol. Chem., 2011, 1508-1515.

24.J. Zou, S. G. Stewart, C. L. Raston; K. S. Iyer, Surface oxygen triggered size change of palladium nano-crystals impedes catalytic efficacy, Chem. Commun., 2011, 47, 1803-1805.

23. J. Bajsa,; A. McCluskey,; C. P Gordon; S. G Stewart; T. A. Hill; R. Sahu,; S. O. Duke; B. L. Tekwani, The antiplasmodial activity of norcantharidin analogues that may act by protein phosphatase inhibition. Bioorg Med Chem Letts, 2010, 20, 6688-6695.

22. S. G. Stewart, C. J. Braun, M. E. Polomska, M. Karimi, L. J. Abraham, K. A. Stubbs, Efforts Toward Elucidating Thalidomides Molecular Target: An Expedient Synthesis of the First Thalidomide Biotin Analogue, Org. Biomol. Chem, 2010, 8, 4059 - 4062.

21. S. G. Stewart, E. L. Ghisalberti, B. W. Skelton, C. H. Heath, Formation and reactions of azepino[4,5-b]indoles: An unprecedented ozone reaction in the formation of novel benzo[c]naphthyridinones, Org. Biomol. Chem, 2010, 8, 3563.

20. H-d Xie, L. A. Ho, M. S. Truelove, B. Corry, S. G. Stewart, Fluorescent Triphenyl Substituted Maleimide Derivatives: Synthesis, Spectroscopy and Quantum Chemical Calculations, J Fluoresc, 2010, 20, 1077–1085.

19.D. L. Priebbenow, L. C. Henderson, F. M. Pfeffer, S. G. Stewart, Domino Heck-aza-Michael reactions; efficient access to 1-substituted tetrahydro-β-carbolines, J. Org. Chem. 2010, 1787-1790.

18.S. G. Stewart, C. J. Braun, S-L. Ng, M. E. Polomska, M. Karimi, L. J. Abraham, New thalidomide analogues derived through Sonogashira or Suzuki reactions and their TNF expression inhibition profiles, Bioorg. Med. Chem. 2010, 18, 650-662.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

6. L. F. Tietze, S. G. Stewart, M. E. Polomska, A. Modi, A. Zeeck, Towards the Synthesis of the New Anticancer Agent Mensacarcin, Chemistry, Eur. J. 2004, 10, 5233.

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.

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.

3. M. G. Banwell, S. G. Stewart, Methyl 6-methoxy-1-oxoindan-4-carboxylate, Org. Prep. Proced. Int, 2001, 33, 177.

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.

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.

Funding received

Cancer Council of Western Australia
Alexander von-Humboldt Stiftung/Foundation
Ada Bartholomew Medical Research Trust Grant
School of Medicine, Dentistry and Health
UWA Priming Grant
Australian Institute of Nuclear Science and Engineering
NH&MRC

Memberships

2009-current Chair, Synthetic and Organic Group (WA-RACI)
2007-current Royal Australian Chemistry Institute Western Australian Committee Member
2004-current Australian Alexander Von Humboldt Society
2005-current Royal Australian Chemistry Institute Member
2006-2008 Exam and course reviewer for Taylors Teaching College

Honours and awards

2010 The Athel Beckwith Lectureship for newly Appointed Staff
2010 Return Alexander von Humboldt Fellowship
2002-2004 Alexander von Humboldt Fellowship

Patents

1. Antimicrobial compounds, A. J. Mckinley; T. V. Riley; N. Lengkeek; S. Stewart; R. Boulos, PCT Int. Appl. (2011), WO 2011075766 A1 20110630.

Teaching

CHEM3306 Modern Organic Synthesis (Course Coordinator)
CHEM3305 Biological Chemistry (Course Coordinator)
CHEM1102 Organic Chemistry (Course Coordinator)

New and noteworthy

Postgraduate Students
(Current)
Charles Heath: The development of new palladium mediated reaction methods towards nitrogen containing heterocyclic compounds (A/Prof Ghisalberti)
Louisa Ho: The total synthesis and biological evaluation of small alkyne epoxide, maleic anhydride, and maleimide natural products (A/Prof Ghisalberti)
Evenda Dench: The total synthesis of the antimalarial natural products, Flinderoles. (Dr Gavin Flematti, Prof Teck-Peng Loh)
James Rixson: The Synthesis and Biological Evaluation of Anthrapyranone Antitumour Antibiotics (Dr Kersten M. Gericke)
Sing Yee Yeung: The Synthesis of Thalidomide Analogues (Prof L Abraham and Dr K Stubbs)
Sven Kampmann: The Synthesis of Novel Thalidomide Derivatives and the Determination of their Molecular Mode of Action (Prof L Abraham)

(Co-Supervised)
Daniel Priebbenow: Palladium mediated domino reactions (Dr Frederick Pfeffer)
Jianli Zou: (Dr. Swaminathan Iyer, Prof Colin Raston)

(Past Students)
Daniel Spagnolo
Rou Wei Lim
Melvin Sin
Sze-Ling Ng
Steffen Meyer
Muhammad Khidir
Carlos Braun
Thomas Chaloner
Ramiz Boulos

Current projects

Small Alkyne Fungal Metabolite Synthesis

Pyrrolesesquiterpene Natural Product Synthesis
Synthesis of Thalidomide Derivatives

Natural Product Synthesis Utilising Palladium Catalysis

Synthesis of Maleic Anhydride and Maleimide Natural Products Found in Antrodia camphorata

The Synthesis of Flinderoles and related compounds for the treatment of Malaria

The preperation of anthrapyranone natural products as highly active antimicrobial and anticancer agents


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
Dr. Kersten Gericke, Bayer Schering Pharma AG

Research profile

Research profile and publications