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 and Hummersone, Marc and Bradshaw, Tracey D. and Zhang, Jihong and Moody, Christopher J. and Foreiter, Magdalena and Summers, Helen and Lewis, William and Wheelhouse, R.T. and Stevens, Malcolm F.G. (2018) 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 . ISSN 2040-2503

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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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Chemistry
University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1039/C7MD00554G
Depositing User: Eprints, Support
Date Deposited: 22 Jan 2018 10:01
Last Modified: 29 May 2018 16:44
URI: http://eprints.nottingham.ac.uk/id/eprint/49226

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