Auckland Cancer Society Research Centre

Medicinal Chemistry - Free Radical Research (FRR) Group

Group leader

Research interests

The Free Radical Research Group, based in the School of Chemical Sciences, collaborates closely with the Medicinal Chemistry Group and the Experimental Oncology Group at the Auckland Cancer Society Research Centre. A variety of projects are undertaken with the common aim to develop improved therapeutic drugs against disease, based on an in depth understanding of the underlying radical mechanisms. While radical reactions are often deleterious to normal cells in the body, they can offer a means to attack certain diseases such as cancer. The two major focuses are:

  • Collaborating with organic chemists and biologists to develop prodrugs which  produce cytotoxic radicals to kill drug-resistant hypoxic cells in solid tumours, and
  • Studying the fast chemical repair of radical-damaged biomolecules by antioxidants to decrease the incidence of diseases associated with aging.

Radical reactions occur very quickly, often on the millionth of a second timescale, requiring fast-detection techniques for their study. The FRR Group uses short pulses (nanosecond to microsecond) of high energy electrons from a 4MeV linear accelerator to initiate radical reactions in the breakdown of aqueous solutions (pulse radiolysis), combined with fast spectrophotometry and conductivity detection for observations to be made in real time. Radical intermediates can also be identified using radical trapping agents followed by electron paramagnetic resonance (EPR) to obtain finger print spectra. Steady-state radiolysis, using a 137Cs g-source, is used to produce products from radical reactions for analysis. The Pulse Radiolysis Facility is a regional resource supporting health-related research by both NZ and Australian scientists under the AINSE program and attracts users and collaborations from wider afield.

Anderson Lab 1
Anderson Lab 2

Current areas of research

Bioreductive drug development

The controlling parameters by which different classes of bioreductive prodrugs are selectively activated to anti-cancer cytotoxins under hypoxia and not in normoxia are studied with medicinal chemists A/Professor Michael Hay, Dr Jeff Smaill, A/Professor Brent Copp, Professor Margaret Brimble and cancer biologists Professor Bill Wilson and A/Professor Adam Patterson. Radical chemistry studies have underpinned mechanistic knowledge in bringing a number of drugs into preclinical and clinical trials, tirapazamine, SN30000, PR104, PR310 and TH-302. Also researched are redox aspects which are important in the activation of anti-tuberculosis drugs with A/Professor Brian Palmer

Radiolytic release of cytotoxins to aid radiotherapy

With advances in the precise delivery of radiotherapy dose fraction to the confines of tumours, it is attractive to design prodrugs to be activated inside the radiation beam to release anticancer cytotoxins. Together with Dr Jeff Smaill and A/Professor Adam Patterson prodrugs, designed to release potent kinase inhibitor upon radiolytic one-electron reduction, are under development.

Fast chemical repair of radical damage by antioxidants

Antioxidants are known to impart health benefits by several mechanisms. We are studying how small concentrations of antioxidants can chemically repair long-lived radicals formed on DNA. The health benefits of constituents of beverages, naturally occurring polyhydroxyphenols and xenobiotics are under study at the molecular level.

Electron transfer in DNA

Understanding the properties of DNA radicals is fundamental to the design of DNA-targeted drugs aimed to counter the deleterious effects of such lesions. The fast chemical repair of these lesions by antioxidants is under study, in particular with Professor Roger Martin of the Peter MacCallum Cancer Institute, Melbourne, Australia on DNA-targeted ligands, which are designed to protect certain normal tissues during radiotherapy.

Superoxide reactions

Superoxide, a by-product of cellular metabolism where oxygen gains an electron, is normally kept at low levels by the superoxide dismutase (SOD) proteins. Its over production is linked to several inflammatory diseases and therapeutics are presently being sought to act as adjuncts to the overwhelmed natural detoxifying systems. The mechanism and kinetic parameters of mitochondria-targeted antioxidants are under study in collaboration with Dr Michael Murphy of the MRC Mitochondrial Unit, Cambridge, UK.

Group Members

Research Students

Current FRR research-lead teaching in papers

CHEM310: Group of SCS students will undertake a research project to investigate the radical chemistry of oxyresveratrol.

FOODSCI201: Introductory lecture on the energetics of antioxidants.

FOODSCI701: Lecture (2 h) on the application of radiation to reduce the incidence food poisoning and other benefits.

FOODSCI703: Lecture (2 h) on reaction of free radicals with cellular and dietary antioxidants.

MEDSCI710: Lecture (2 h) a radical view on the health benefits of antioxidants.

Available student research projects

  • Factors controlling the release of cytotoxins from anticancer prodrugs.
  • Fast chemical repair of DNA radicals by nitroxide antioxidants.
  • Mechanism of radioprotection afforded by DNA-binding bisbenzimidazole ligands.

Recent publications

2014 Anderson, R.F., Yadav, P., Patel, D., Reynisson, J., Tipparaju, S., Guise, C., Patterson, A. V., Denny, W.A., Maroz, A., Shinde, S.S. and Hay, M.P. Characterisation of radicals formed by the triazine 1,4-dioxide hypoxia-activated prodrug, SN30000. Org. Biomolec. Chem. 12, 3386-3392.

2014 Anderson, R.F., Shinde, S.S., Hille, R., Rothery, R.A. Weiner, J.H., Rajagukguk, S., Maklashina, E. and Cecchini, G. Electron transfer pathways in the heme and quinone binding domain of Complex II (succinate dehydrogenase). Biochemistry, 53, 1637-1646.

2014 Bonnet, M., Hong, C.R., Gu, Y., Anderson, R.F., Wilson, W.R., Pruijn, F.B., Wang, J., Hicks, K.O. and Hay, M.P. Novel nitroimidazole sulfonamides as hypoxic cell radiosensitizers. Org. Biomolec. Chem. 22, 2123-2132.

2013 Rathod, M.A., Patel, D., Das, A., Tipparaju, S.R., Shinde, S.S. and Anderson, R.F. Inhibition of radical-induced DNA strand breaks by water-soluble constituents of coffee: Phenolics and caffeine metabolites. Free Radic. Res.46, 480-7.

2013 Lu, G.-L., Ashoorzadeh, A., Anderson, R.F., Patterson, A.V. and Smaill, J.B. Synthesis of substituted 5-bromomethyl-4-nitroimidazoles and use for the preparation of the hypoxia-selective multikinase inhibitor SN29966. Tetrahedron, 69, 9130-9138.

2012 Pattison, D.I., Lam, M., Shinde, S.S., Anderson, R.F. and Davies, M.J. The nitroxide, TEMPO, is an efficient scavenger of protein radicals: Cellular and kinetic studies. Free Radic. Biol. Med., 53, 1664-1674.

2012 Kelso, G.F., Maroz, A., Cocheme, H.M., Logan, A., Prime, T.A., Peskin, A.V., Winterbourn, C.C., James, A.M., Ross, M.F., Brooker, S.A.., Porteous, C.M., Anderson, R.F., Murphy, M.P. and Smith, R.A.J. A mitochondria-targeted macrocyclic superoxide dismutase mimetic. Chemistry & Biology, 19, 1237-1256.

2012 Meng, F., Evans, J.W., Bhupathi, D., Banica, M., Lan, L., Lorente, G., Duan, J.-X., Cai, X., Mowday, A.M., Guise, C.P., Maroz, A., Anderson, R.F., Patterson, A.V., Stachelek, G.C., Glazer, P.M., Matteucci, M.D. and Hart, C.P. Molecular and cellular pharmacology of the hypoxia-activated prodrug TH-302. Mol. Cancer Ther. 11, 740-751.