Antitumor imidazo[5,1-d]-1,2,3,5-tetrazines: compounds modified at the 3-position overcome resistance in human glioblastoma cell lines

Cousin, David; Zhang, Jihong; Hummersone, Marc G.; Matthews, Charles S.; Frigerio, Mark; Bradshaw, Tracey; Stevens, Malcolm F.G.

Abstract

Synthetic routes to 3-substituted imidazo[5,1-d]-1,2,3,5-tetrazines structurally related to temozolomide were explored. Interaction of 4-diazoimidazole-5-carboxamide with an isocyanate afforded high product yields when the isocyanate was available in acceptable purity. Alternatively, alkylation of the nor-temozolomide anion afforded high yields of new imidazotetrazines. Several compounds, evaluated against a panel containing matched MGMT± glioma cell lines, showed equal inhibitory activity irrespective of MGMT status; the N3-propargyl-imidazotetrazine (10m) was prioritised as an alternative to temozolomide able to bypass drug-resistance mechanisms. In Taq polymerase assays 10m, like temozolomide and its ring-opened counterpart MTIC, alkylated DNA at clusters of three and five guanine residues; covalent modification of N-7 sites of guanine were detected in piperidine cleavage assays. Compound 10m did not cross-link DNA but induced double-strand breaks evidenced by γ-H2AX detection. Propargyl-substituted imidazotriazene (13g), showed comparable activity to 10m indicating that ring-opening of the bicyclic nucleus of novel imidazotetrazine is probably required for activity.

• Journal Article Type: Article
• Acceptance Date: Sep 15, 2016
• Online Publication Date: Sep 20, 2016
• Publication Date: Dec 1, 2016
• Deposit Date: Sep 14, 2017
• Print ISSN: 2040-2503
• Electronic ISSN: 2040-2511
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 7
• Issue: 12
• Pages: 2332-2343
• DOI: https://doi.org/10.1039/c6md00384b
• Public URL: https://nottingham-repository.worktribe.com/output/1121358
• Publisher URL: https://pubs.rsc.org/en/Content/ArticleLanding/2016/MD/C6MD00384B#!divAbstract
• PMID: 00039055