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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

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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.

Graphical abstract: 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

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Publication details

The article was received on 01 Nov 2017, accepted on 12 Jan 2018 and first published on 19 Jan 2018


Article type: Research Article
DOI: 10.1039/C7MD00554G
Citation: Med. Chem. Commun., 2018, Advance Article
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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

    D. Cousin, M. G. Hummersone, T. D. Bradshaw, J. Zhang, C. J. Moody, M. B. Foreiter, H. S. Summers, W. Lewis, R. T. Wheelhouse and M. F. G. Stevens, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C7MD00554G

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