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.

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., Summers, H., Lewis, W., Wheelhouse, R., & 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: 2040-2511
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1039/C7MD00554G
• Public URL: https://nottingham-repository.worktribe.com/output/905766
• Publisher URL: http://pubs.rsc.org/en/content/articlepdf/2018/md/c7md00554g
• Contract Date: Jan 22, 2018