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Synthesis and growth-inhibitory activities of imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position

Cousin, David; Hummersone, Marc; Bradshaw, Tracey D.; Zhang, Jihong; Moody, Christopher J.; Foreiter, Magdalena; Summers, Helen; Lewis, William; Wheelhouse, R.T.; Stevens, Malcolm F.G.

Authors

David Cousin

Marc Hummersone

Jihong Zhang

Christopher J. Moody

Magdalena Foreiter

Helen Summers Helen.Summers@nottingham.ac.uk

William Lewis

R.T. Wheelhouse

Malcolm F.G. Stevens malcolm.stevens@nottingham.ac.uk



Abstract

A series of 3-(benzyl-substituted)-imidazo[5,1-d]-1,2,3,5-tetrazines (13) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity in vitro against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI50 values > 50 μM against both sets of cell lines. Two silicon-containing derivatives, the TMS-methylimidazotetrazine (9) and the SEM-analogue (10), showed interesting differences: compound (9) had a profile very similar to that of temozolomide with the MGMT+ cell lines being 5 to 10-fold more resistant than MGMT– isogenic partners; the SEM-substituted compound (10) showed potency across all cell lines irrespective of their MGMT status.

Citation

Cousin, D., Hummersone, M., Bradshaw, T. D., Zhang, J., Moody, C. J., Foreiter, M., …Stevens, M. F. (in press). Synthesis and growth-inhibitory activities of imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamides related to the anti-tumour drug temozolomide, with appended silicon, benzyl and heteromethyl groups at the 3-position. MedChemComm, https://doi.org/10.1039/C7MD00554G

Journal Article Type Article
Acceptance Date Jan 12, 2018
Online Publication Date Jan 19, 2018
Deposit Date Jan 22, 2018
Publicly Available Date Jan 20, 2019
Journal MedChemComm
Print ISSN 2040-2503
Electronic ISSN 2040-2503
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1039/C7MD00554G
Public URL http://eprints.nottingham.ac.uk/id/eprint/49226
Publisher URL http://pubs.rsc.org/en/content/articlepdf/2018/md/c7md00554g
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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