Group leader
Current research
Cancer chemotherapy was founded on agents that interact with or alkylate DNA, and
such compounds continue to be clinically important today. Their major limitation
is a lack of selectivity, as they tend to target rapidly dividing cells which are
present in but not limited to tumour tissue. Opportunities exist to enhance the
therapeutic window of such agents by making them more selective – either by selectively
targeting particular DNA sequences (oncogenes, transcription factors), or alternatively
by selective activation in or delivery to tumour tissue.
We have an ongoing interest in DNA alkylating agents of the cyclopropylindoline
class – synthetic analogues of potent minor groove alkylating natural products such
as CC-1065 and the duocarmycins. By substitution of a key phenol in the active pharmacophore
with an amino group we have created a new set of DNA alkylating agents.
These have similar properties to the natural products (sequence selective alkylation
at N3 of adenine and high cytotoxic potency) but lend themselves to the formation
of prodrugs which can be selectively activated in the tumour microenvironment. For
example SN 26438 is a prototype nitro prodrug which is activated by bioreduction
and is selectively
toxic to hypoxic cells in human tumour xenografts.
Investigation of this and related compounds is currently being pursued under a
New Economy Research Fund project in collaboration
with Dr Frederik Pruijn of the Experimental Therapeutics Group.
Dr Frederik Pruijn
Experimental
Therapeutics Group
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Fig 1: Molecular modelling of non-covalent binding of the spirocyclopropyl form
of the natural enantiomer of the aminocyclopropylindoline derived from SN 26438,
docked in an oligomer with a single high affinity duocarmycin binding site (d-(GACTAATTGAC)
d-(GTCATTAGTC). |
Other
research interests
- Radiation-activated prodrugs, including quaternary salt and metal complex prodrugs
of cyclopropylindolines.
- Sequence selective DNA cross-linking agents, for example agents combining cyclopropylindolines
and pyrrolobenzodiazepines.
- The remarkable weight loss induced in mice following a single non-toxic treatment with particular cyclopropylindoline derivatives. This investigation is being carried
out in collaboration with the Department of Physiology's Dr Kathy Mountjoy.
- Novel 2-nitroimidazoles for the detection of hypoxic cells
Dr Kathy Mountjoy
Publications
- Tercel, M., Atwell, G.J., Yang, S., Stevenson, R.J., Botting, K.J., Boyd, M., Smith,
E., Anderson, R.F., Denny, W.A., Wilson, W.R., Pruijn, F.B. Hypoxia-activated prodrugs:
substituent effects on the properties of nitro seco-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one
(nitroCBI) prodrugs of DNA minor groove alkylating agents. J. Med. Chem., 2009,
52, 7258-7272.
- Wilson, W.R., Stribbling, S.M., Pruijn, F.B., Syddall, S.P., Patterson, A.V., Liyanage,
H.D.S., Smith, E., Botting, K.J., Tercel, M. Nitro-chloromethylbenzindolines: hypoxia-activated
prodrugs of potent adenine N3 DNA minor groove alkylators. Mol. Cancer Ther., 2009,
8, 2903-2913.
- Milbank, J.B., Stevenson, R.J., Ware, D.C., Chang, J.Y., Tercel, M., Ahn, G.O.,
Wilson, W.R., Denny, W.A. Synthesis and evaluation of stable bidentate transition
metal complexes of 1-(chloromethyl)-5-hydroxy-3-(5,6,7-trimethoxyindol-2-ylcarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline
(seco-6-azaCBI-TMI) as hypoxia selective cytotoxins. J. Med. Chem. 2009, 52, 6822-6834.
- Ahn, G., Botting, K.J., Patterson, A.V., Ware, D.C., Tercel, M. and Wilson W.R.
Radiolytic and cellular reduction of a novel hypoxia-activated cobalt(III) prodrug
of a chloromethylbenzindoline DNA minor groove alkylator. Biochem. Pharmacol., 2006,
71, 1683-1694.
- Tercel, M., Stribbling, S.M., Sheppard, H., Siim, B. G., Wu, K.,
Pullen, S.M., Botting, J., Wilson, W.R., Denny, W.A. Unsymmetrical DNA Cross-Linking
Agents: Combination of the CBI and PBD Pharmacophores. J. Med. Chem., 2003, 46,
2132-2151.
- Tercel, M., Gieseg, M.A., Milbank, J.B., Boyd, M., Fan, J-Y., Tan,
K.L., Wilson, W.R., Denny, W.A. Cytotoxicity and DNA interaction of the enantiomers
of 6-amino-3-(chloromethyl)-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]indoline (Amino-seco-CI-TMI).
Chem. Res. Toxicol., 1999, 12, 700-706.
- Tercel, M., Gieseg, M.A., Denny,
W.A., Wilson, W.R. Synthesis and cytotoxicity of amino-seco DSA: an amino analogue of
the DNA alkylating agent duocarmycin SA. J. Org. Chem., 1999, 64, 5946-5953.
- Atwell,
G.J., Tercel, M., Boyd, M., Wilson, W.R., Denny, W.A. Synthesis and cytotoxicity
of 5-amino-1-(chloromethyl)-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-benz[e]indole
(amino-seco-CBI-TMI) and related 5-alkylamino analogues: new DNA minor groove alkylating
agents. J. Org. Chem., 1998, 63, 9414-9420.
Group members
