Dr Catherine H Kaschula
My broad research aim is to use a multi-disciplinary approach to understand the mechanisms behind the cancer preventative properties of natural dietary compounds. Specific compounds of interest have included disulfides from garlic, isothiocyanates from coniferous vegetables and flavonoids which are found in a variety of edible and medicinal plants. I have a fundamental training in synthetic organic and medicinal chemistry but have many years of experience in the biological sciences. I therefore work at the interface of chemistry and biology where I use synthesis as a tool to unravel the chemistry occurring between a small molecule and its biological environment. I am particularly interested in identifying the pharmacophore of natural dietary compounds which gives rise to their cytotoxicity in cancer cells. We have synthesized a number of tagged compounds to probe mechanism and to identify their protein targets in cancer cells.
Garlic belongs to the lily family with a botanical name Allium sativum. It is derived from the Celtic word “all” meaning pungent. The pungency arises from a group of small, volatile sulfur-containing compounds which are generated be the plant in chemical defence against invasive threats. These compounds are biologically active and in many respects mimic the small molecule glutathione. The chemistry of garlic involves the coming together of the enzyme alliinase and its substrate alliin when the clove is damaged to produce allicin. Allicin is unstable and can self-react to form a number of relatively stable secondary compounds which include ajoene. Ajoene is a bioactive molecule with cancer preventative properties. The allicin to ajoene transformation can take place slowly at room temperature but occurs rapidly when allicin is heated (ie cooked garlic).
Freshly cooked garlic
Cooked or aged garlic
In our work we have established that the disulfide functional group in ajoene is the pharmacophore responsible for S-thiolating a cysteine residue in a redox-sensitive protein resulting in S-allyl transfer to the protein (shown below). In many cases, this results in a functional change in the protein or inactivation of an enzyme to bring about the biological effect. We have developed the first synthetic route to ajoene analogues which has enabled us to synthesize useful compounds including fluorescently-tagged ajoenes. These tagged ajoenes helped us to track ajoene to the endoplasmic reticulum in cancer cells where we found it interferes with protein folding. Current work centres on synthesizing biotinylated ajoene analogues which we will use to identify the specific protein targets of ajoene in cancer cells. We are also synthesizing ajoene analogues with improved pharmacokinetic profiles which may be useful in combination with clinical cancer drugs.
(1). Smith, M., Hunter, R., Stellenboom, N., Kusza, D.A., Parker, M.I., Hammouda, A. N. H., Jackson, G., Kaschula, C. H. The cytotoxicity of garlic-related disulfides and thiosulfonates in WHCO1 oesophageal cancer cells is dependent on S-thiolation and not production of ROS. Biochim. Biophys. Acta. 2016, 1860 (216), 1439-1449.
(2). Kaschula, C.H., Hunter, R., Cotton, J., Tuveri, R., Dzobo, K., Ngarande, E., Schäfer, G., Siyo, V., Lang, D., Kusza, D.A., Davies, B., Katz, A., Parker, M.I. The Garlic Compound Ajoene Targets Protein Folding in the Endoplasmic Reticulum of Cancer Cells. Mol. Carcinogen. 2015, Online ahead of print.
(3). Schäfer, G., Kaschula, C.H. The Immunomodulation and Anti-Inflammatory Effects of Garlic Organosulfur Compounds in Cancer Chemoprevention. Anti-Cancer Agent Med. Chem. 2014, 14 (2), 233-240.
(4). Kaschula, C. H., Hunter, R., Stellenboom, N., Caira, M. R., Winks, S., Ogunleye, T., Richards, P., Cotton, J., Zilbeyaz, K., Wang, Y., Siyo, V., Parker, M. I. Structure-Activity Studies on the Anti-Proliferation Activity of Synthetic Ajoene Derivatives in WHCO1 Oesophageal Cancer Cells. Eur. J. Med. Chem. 2012, 50, 236-254.
(5). Kaschula, C. H., Hunter, R., Parker, M. I., Hassan, H.T., Stellenboom, N., Cotton, J., Zhai, X.Q. Synthesis and Anti-Proliferation Efficacy of Synthetic Ajoene Analogues in Cancer Cells. Anti-Cancer Agent Med. Chem. 2011, 11 (3), 260-266.
(6). Macedo, B., Kaschula, C. H., Hunter, R., Chaves, J. A. P., van der Merwe, J.D., Silva, J. L., Egan, T. J., Cordeiro, Y. Synthesis and anti-prion activity evaluation of aminoquinoline analogues. Eur. J. Med. Chem. 2010, 45, 5468-5473.
(7). Kaschula, C. H., Hunter, R., Parker, M. I. Garlic-Derived Anti-Cancer Agents: Structure and Biological Activity of Ajoene. Biofactors. 2010, 36 (1), 78-85.
(8). Hunter, R., Kaschula, C. H., Parker, M. I., Caira, M.R., Richards, P., Travis, S., Taute, F., Qwebani, T. Substituted ajoenes as novel anti-cancer agents. Bioorg. Med. Chem. Lett. 2008, 18 (19), 5277-5279.
(9). De Villiers, K. A., Kaschula, C. H., Egan, T. J., Marques, H. M. Speciation and Structure of Ferriprotoporphyrin IX in Aqueous Solution: Spectroscopic and Diffusion Measurements Demonstrate Dimerization, but not µ-oxo Dimer Formation. J. Biol. Inorg. Chem. 2007, 12, 101–117.
(10). Kaschula, C. H., Egan, T. J., Hunter, R., Basilico, N., Parapini, S., Taramelli, D., Pasini, E., Monti, D. Structure – Function Relationships in 4-Aminoquinolines Antiplasmodials. The Role of the Group at the 7-Position. J. Med. Chem. 2002, 45, 3531–3539.
(11). Kaschula, C. H., Egan, T. J., Hunter, R., Marques, H. M., Misplon, A., Walden, J. Structure – Function Relationships in Aminoquinolines: Effect of Amino and Chloro Groups on Quinoline – Haematin Complex Formation, Inhibition of [Symbol]-Haematin Formation, and Antiplasmodial Activity. J. Med. Chem. 2000, 43, 283–291.