Modulation of the acidity of the 8-carboxamide group in the temozolomide family of antitumor imidazo[5,1-d][1,2,3,5]tetrazines

Summers, Helen S.; Foreiter, Magdalena B.; Lewis, William; Moody, Christopher J.; Bradshaw, Tracey D.; Stevens, Malcolm F.G.

Abstract

Imidazo[5,1-d][1,2,3,5]tetrazines related in structure to the anticancer drugs temozolomide and mitozolomide with modification of the 8-carboxamide group, have been synthesized, N-nitrocarboxamides by direct nitration of the corresponding carboxamides, and N-cyanomitazolomide by sodium cyanamide acylation. The NH groups in the N-nitro- and N-cyano-carboxamides were considerably more acidic than the parent carboxamide, and readily formed salts with morpholine and imidazole. X-Ray crystallography revealed that the N-nitro compound existed as such rather than the nitronic acid tautomer. Preliminary evaluation showed that enhancing the acidity of the carboxamide NH in mitozolomide analogues was detrimental to the growth inhibitory activity.

Citation

Summers, H. S., Foreiter, M. B., Lewis, W., Moody, C. J., Bradshaw, T. D., & Stevens, M. F. (2020). Modulation of the acidity of the 8-carboxamide group in the temozolomide family of antitumor imidazo[5,1-d][1,2,3,5]tetrazines. Arkivoc, 2020(7), 36-45. https://doi.org/10.24820/ARK.5550190.P011.182

• Journal Article Type: Article
• Acceptance Date: Apr 28, 2020
• Online Publication Date: May 6, 2020
• Publication Date: 2020
• Deposit Date: Jan 15, 2024
• Publicly Available Date: Jan 17, 2024
• Journal: Arkivoc
• Print ISSN: 1551-7012
• Electronic ISSN: 1551-7004
• Publisher: Michigan Publishing
• Peer Reviewed: Peer Reviewed
• Volume: 2020
• Issue: 7
• Pages: 36-45
• DOI: https://doi.org/10.24820/ARK.5550190.P011.182
• Keywords: Heterocyclic antitumor agents, imidazotetrazine, temozolomide, carboxamide acidity
• Public URL: https://nottingham-repository.worktribe.com/output/8309900
• Publisher URL: https://www.arkat-usa.org/arkivoc-journal/browse-arkivoc/ark.5550190.p011.182