Prof Tom Simpson's Research
BIO-ORGANIC AND NATURAL PRODUCT
- Polyketide antibiotics.
The polyketide biosynthetic pathway is responsible for the production of
many antibiotics and other compounds of medicinal and agrochemical
importance in a wide range of micro-organisms and higher plants. A
multidisciplinary group is studying all aspects of the chemistry -
isolation and structure elucidation, total synthesis and biosynthesis - of
polyketide metabolites. Compounds currently being investigated include the
antibiotic, pseudomonic acid (1), the immunosuppressive agent, rapamycin
(2), squalestatin (3) which acts to lower blood cholesterol levels, and
the insecticidal and fungicidal metabolite monocerin (4). Recent advances
in genetics have enabled the biosynthetic enzymes to be isolated in
sufficient quantities for mechanistic and structural studies. Projects are
available which include total synthesis, synthesis of biosynthetic
intermediates and enzyme substrates in isotopically labelled form,
structure elucidation of novel compounds produced by genetically modified
micro-organisms, and isolation and structural studies (high field NMR and
molecular graphics) of biosynthetic enzymes. Much of the work in this area
involves collaboration with pharmaceutical and agrochemical companies in
the UK, Europe and USA, and with scientists from a wide range of
disciplines, including microbiology, molecular genetics and biochemistry.
- Synthesis of
biologically active natural products. Work in this area includes the
total synthesis of aromatic and quinonoid compounds. Synthetic
methodologies based on cycloaddition reactions of substituted pyrones and
carbohydrate synthons are being developed.
- Chemistry and
biosynthesis of mycotoxins. Mycotoxins are produced as a result of
infestation of foodstuffs by certain fungi. Aspects being studied include
synthesis of advanced intermediates for biosynthetic studies; synthesis of
antigens for antibody generation; the effect of specific enzyme inhibitors
on biosynthetic pathways; and chemical and biological degradation of
- Novel polymers. The
synthesis of novel polymers based upon substituted biphenyls and
polyphenyls is being studied.
"Applications of Multinuclear NMR to Structural and Biosynthetic Studies
of Polyketide Microbial Metabolites", Chem. Soc. Review, 1987, 16,
T.J. Simpson and C.L. Willis, "Biosynthesis of Colletodiol and Related
Polyketide Macrodiolides in Cytospora sp. ATCC 20502: Synthesis and
Metabolism of Advanced Intermediates", J. Chem. Soc., Chem. Comm.,
T.J. Simpson and C.L. Willis, "Structures of Bartanol and Iso-bartanol,
Novel Macrodiolide Metabolites from Cytospora sp ATCC 20502", J.
Chem. Soc., Perkin Trans. 1, 1994, 2493-2497
"Polyketide Biosynthesis", Chem. Ind., 1995, 407-411; J.A.
O'Neill, S.D. Lindell, T.J. Simpson and C.L. Willis, "Enantioselective
Synthesis of the 13-Membered Macrodiolide Bartanol", J. Chem. Soc.,
Perkin Trans. 1, 1996, 632-644.
C. McNicholas, T.J. Simpson and N.J. Willett, "Biosynthesis of
Norsolorinic Acid and Averufin: Substrate Specificity of Norsolorinic Acid
Synthase", J. Chem. Soc., Chem. Commun., 1996, 301-302.
T.J. Simpson and N.J. Willett, "Enantioselective Synthesis of Fusarentin
Methyl Ethers: Insecticidal Metabolites of Fusarium larvarum",
Tetrahedron Lett., 1996, 37, 8053-8056.
M.P. Crump, J.
Crosby, C.E. Dempsey, J.A. Parkinson, M. Murray, D.A. Hopwood and T.J. Simpson,
"The Solution Structure of the Actinorhodin Polyketide Synthase Acyl
Carrier Protein from Streptomyces coelicolor A3(2)",
Biochemistry, 1997, 36, 6000-6008.
- T.J. Simpson, R.W. Smith, S.M.Westaway, C.L. Willis, A.D. Buss,
R.J.P. Cannell, M.J. Dawson and B.A.M. Rudd, "Enantioselective
Synthesis of a Putative Hexaketide Intermediate in the Biosynthesis of the
Squalestatins", Tetrahedron Lett., 1997, 38,
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