Senior Lecturer in Medicinal Chemistry
5 West – 3.8
Tel: +44 (0) 1225 383101
Dr Ian M. Eggleston
The general focus of our research is in synthetic organic chemistry and its application to problems in biology and medicine. We are particularly interested in the preparation of biologically active peptides and polyamines, and other small molecules as novel inhibitors or mechanistic probes for enzymes that are targets of therapeutic importance in the field of antifungals, asthma, and tropical disease. We also work on peptide-based prodrugs for use in selective light-activated treatment of cancer and infectious diseases, and have a longstanding interest in the anticarcinogenic properties of phytochemicals. Some of our current research projects include:
Chitinases and Carbohydrate Esterases
Chitin, a polymer of beta(1,4)-N-acetylglucosamine, is an essential structural component of fungal cell walls, nematode egg shells and arthropod exoskeletons. Family 18 chitinases, which degrade this polymer, have recently been validated as attractive targets for the development of inhibitors with chemotherapeutic potential against pathogenic fungi, insects and protozoan/nematodal parasites, and possibly inflammatory disorders such as asthma. We have recently synthesised two families of cyclic peptide natural products which have been identified as potent chitinase inhibitors, and in collaboration with the group of Prof. Daan van Aalten (University of Dundee), we are working on the X-ray structure-based design of novel inhibitors derived from these scaffolds, as well other drug-like chitinase inhibitors, based on a “dicaffeine” motif.
Family 4 carbohydrate esterases are enzymes that de-N-acetylate carbohydrate polymers such as chitin in the cell walls of microbial pathogens. This may allow these organisms to evade the action of carbohydrate-processing enzymes from the human immune system. In collaboration with Prof. van Aalten, we are also preparing chemical probes for these enzymes, in order to better understand their mechanisms and functions.
Trypanothione Reductase Inhibitors
Trypanothione reductase is an important, validated target for the design of new drugs to combat tropical parasitic diseases such as African sleeping sickness, Chagas’ disease, and leishmaniasis. We have synthesised various polyamine derivatives, based on natural product leads which have been screened for anti-TryR activity in collaboration with the group of Prof. Alan Fairlamb in Dundee. Some of these show significant in vitro antitrypanosomal activity and may serve as leads for developing new antitrypanosomal agents. We are also interested in polyamine-based inhibitors of other trypanothione-dependent enzymes which may be potential drug targets in antiparasitic chemotherapy.
Novel Peptide Prodrugs for ALA-PDT
Photodynamic therapy (PDT) is an emerging therapy for the treatment of cancer and various other human disorders. In PDT, destruction of tumours or pathogenic organisms is achieved with light following the administration of a light-activated photosensitising drug which is ideally selectively retained in, or targeted to, diseased tissue relative to normal adjacent tissue. The exogenous administration of 5-aminolaevulinic acid (ALA) has attracted considerable interest for PDT since it is a naturally occurring compound present in prokaryotic and eukaryotic cells which can be metabolised to a porphyrin photosensitiser, protoporphyrin IX (PpIX) via the haem biosynthetic pathway. ALA-PDT is a powerful approach for both the detection and treatment of cancers, and also has considerable potential for use in antimicrobial applications since various Gram-positive and Gram-negative bacteria, yeasts and fungi are able to assimilate exogenous ALA for porphyrin synthesis, thus rendering them susceptible to photosensitisation. A key challenge in ALA-PDT is to improve the efficiency of ALA delivery, since the zwitterionic nature of ALA itself at physiological pH limits its passage through cellular membranes and other biological barriers. The selective delivery and release of ALA in specific tissues is also currently difficult to achieve. In collaboration with Dr Sandy MacRobert and Professor Michael Wilson (University College London), we are preparing novel ALA-containing peptide prodrugs with improved cellular uptake and targeting properties and investigating the effectiveness of these compounds in a variety of cell lines and microorganisms.
Schimpl, M., Rush, C. l., Betou, M., Eggleston, I. M., Recklies, A. d. and Van aalten, D. m. F., 2012. Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. Biochemical Journal, 446 (1), pp. 149-157.
Wang, J. T. -W., Giuntini, F., Eggleston, I. M., Bown, S. G. and MacRobert, A. J., 2012. Photochemical internalisation of a macromolecular protein toxin using a cell penetrating peptide-photosensitiser conjugate. Journal of Controlled Release, 157 (2), pp. 305-313.
Arrowsmith, R. L., Zeglis, B. M., Viola-Villegas, N., Divilov, V., Jones, M., Waghorn, P. A., Phillips, F. L., Mindt, T. L., Eggleston, I. M., Botchway, S. W., Dilworth, J. R., Aigbirhio, F. I., Lewis, J. S. and Pascu, S. I., 2011. Fluorescent copper(II), gallium(III) and indium(III) bis(thiosemicarbazonates): radiolabeling, cellular confocal fluorescence and PET imaging studies. Journal of Labelled Compounds & Radiopharmaceuticals, 54 (Supplement 1), S59.
Sutherland, T. E., Andersen, O. A., Betou, M., Eggleston, I. M., Maizels, R. M., van Aalten, D. and Allen, J. E., 2011. Analyzing airway inflammation with chemical biology: Dissection of acidic mammalian chitinase function with a selective drug-like inhibitor. Chemistry & Biology, 18 (5), pp. 569-579.
Webb, C., Upadhyay, A., Giuntini, F., Eggleston, I., Furutani-Seiki, M., Ishima, R. and Bagby, S., 2011. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway. Biochemistry, 50 (16), pp. 3300-3309.
Rush, C. L., Schuttelkopf, A. W., Hurtado-Guerrero, R., Blair, D. E., Ibrahim, A. F. M., Desvergnes, S., Eggleston, I. M. and van Aalten, D. M. F., 2010. Natural Product-Guided Discovery of a Fungal Chitinase Inhibitor. Chemistry & Biology, 17 (12), pp. 1275-1281.
Reelfs, O., Eggleston, I. M. and Pourzand, C., 2010. Skin protection against UVA-induced iron damage by multiantioxidants and iron chelating drugs/prodrugs. Current Drug Metabolism, 11 (3), pp. 242-249.
Bourre, L., Giuntini, F., Eggleston, I. M., Mosse, C. A., MacRobert, A. J. and Wilson, M., 2010. Effective photoinactivation of Gram-positive and Gram-negative bacterial strains using an HIV-1 Tat peptide-porphyrin conjugate. Photochemical & Photobiological Sciences, 9 (12), pp. 1613-1620.
Giuntini, F., Bourre, L., MacRobert, A. J., Wilson, M. and Eggleston, I. M., 2009. Improved peptide prodrugs of 5-ALA for PDT: rationalization of cellular accumulation and protoporphyrin IX production by direct determination of cellular prodrug uptake and prodrug metabolization. Journal of Medicinal Chemistry, 52 (13), pp. 4026-4037.
Higgins, L. G., Kelleher, M. O., Eggleston, I. M., Itoh, K., Yamamoto, M. and Hayes, J. D., 2009. Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicology and Applied Pharmacology, 237 (3), pp. 267-280.
Dixon, M. J., Nathubhai, A., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold. Organic and Biomolecular Chemistry, 7 (2), pp. 259-268.
Kelleher, M. O., McMahon, M., Eggleston, I. M., Dixon, M. J., Taguchi, K., Yamamoto, M. and Hayes, J. D., 2009. 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein. Carcinogenesis, 30 (10), pp. 1754-1762.
Bourre, L., Giuntini, F., Eggleston, I. M., Wilson, M. and MacRobert, A. J., 2009. Protoporphyrin IX enhancement by 5-aminolaevulinic acid peptide derivatives and the effect of RNA silencing on intracellular metabolism. British Journal of Cancer, 100 (5), pp. 723-731.
Dixon, M. J., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. SPPS of the natural product chitinase inhibitor argifin: library generation and biological evaluation. In: Del Valle, S., Escher, E. and Lubell, W. D., eds. Peptides for Youth. Vol. 611. New York: Springer, pp. 143-144.
Dixon, M. J., Nathubhai, A., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2009. Synthesis and Structure-based Dissection of Cyclic Peptide Chitinase Inhibitors: New Leads for Antifungal and Anti-inflammatory Drugs. In: DelValle, S., Escher, E. and Lubell, W. D., eds. Peptides for Youth - The Proceedings of the 20th American Peptide Symposium. Springer, pp. 525-526.
Giuntini, F., Bourre, L., Wilson, M., MacRobert, A. J. and Eggleston, I. M., 2008. A novel approach to improve cellular delivery of 5-aminolaevulinic acid: New ALA-containing peptide Prodrugs for photodynamic therapy. Journal of Peptide Science, 14 (8 (Suppl S)), p. 156.
Dixon, M., Giuntini, F., Nathubhai, A., Andersen, O., van Aalten, D. and Eggleston, I., 2008. Synthetic approaches to cyclic peptide natural products as chitinase inhibitors. Journal of Peptide Science, 14 (8), p. 55.
Andersen, O. A., Nathubhai, A., Dixon, M. J., Eggleston, I. M. and van Aalten, D. M. F., 2008. Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin. Chemistry & Biology, 15 (3), pp. 295-301.
Bourre, L., Giuntini, F., Eggleston, I. M., Wilson, M. and MacRobert, A. J., 2008. 5-aminolaevulinic acid peptide prodrugs enhance photosensitization for photodynamic therapy. Molecular Cancer Therapeutics, 7 (6), pp. 1720-1729.
Paterson, M. J. and Eggleston, I. M., 2008. Convenient preparation of N-maleoyl amino acid succinimido esters using N-trifluoroacetoxysuccinimide. Synthetic Communications, 38 (2), pp. 303-308.
Giuntini, F., Bourre, L., MacRobert, A. J., Wilson, M. and Eggleston, I. M., 2008. Quantitative determination of 5-aminolaevulinic acid and its esters in cell lysates by HPLC-fluorescence. Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences, 875 (2), pp. 562-566.
Dixon, M., Nathubhai, A., Andersen, O., van Aalten, D. and Eggleston, I. M., 2008. Synthesis of cyclic peptide chitinase inhibitors: Natural products,with chemotherapeutic potential. Journal of Peptide Science, 14 (8 (Suppl S)), p. 13.
Hayes, J. D., Kelleher, M. O. and Eggleston, I. M., 2008. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. European Journal of Nutrition, 47, pp. 73-88.