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. 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
RIS ID: https://nottingham-repository.worktribe.com/output/905766
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Chemistry
University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: 10.1039/C7MD00554G
Depositing User: Eprints, Support
Date Deposited: 22 Jan 2018 10:01
Last Modified: 04 May 2020 19:27
URI: https://eprints.nottingham.ac.uk/id/eprint/49226

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