Discovery of new imidazotetrazinones with potential to overcome tumor resistance

Summers, Helen S.; Lewis, William; Williams, Huw E. L.; Bradshaw, Tracey D.; Moody, Christopher J.; Stevens, Malcolm F. G.

Abstract

We describe the design, organic synthesis, and characterization, including X-ray crystallography, of a series of novel analogues of the clinically used antitumor agent temozolomide, together with their in vitro biological evaluation. The work has resulted in the discovery of a new series of anticancer imidazotetrazines that offer the potential to overcome the resistance mounted by tumors against temozolomide. The rationally designed compounds that incorporate a propargyl alkylating moiety and a thiazole ring as isosteric replacement for a carboxamide, are readily synthesized (gram-scale), exhibit defined solid-state structures, and enhanced growth-inhibitory activity against human tumor cell lines, including MGMT-expressing and MMR-deficient lines, molecular features that confer tumor resistance. The cell proliferation data were confirmed by clonogenic cell survival assays, and DNA flow cytometry analysis was undertaken to determine the effects of new analogues on cell cycle progression. Detailed 1H NMR spectroscopic studies showed that the new agents are stable in solution, and confirmed their mechanism of action. The propargyl and thiazole substituents significantly improve potency and physicochemical, drug metabolism and permeability properties, suggesting that the thiazole 13 should be prioritized for further preclinical evaluation.

• Journal Article Type: Article
• Acceptance Date: May 18, 2023
• Online Publication Date: May 30, 2023
• Publication Date: Sep 5, 2023
• Deposit Date: May 22, 2023
• Publicly Available Date: Jun 7, 2023
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Electronic ISSN: 1768-3254
• Publisher: Elsevier BV
• Peer Reviewed: Peer Reviewed
• Volume: 257
• Article Number: 115507
• DOI: https://doi.org/10.1016/j.ejmech.2023.115507
• Keywords: Organic Chemistry; Drug Discovery; Pharmacology; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/21100715
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523423004737?via%3Dihub