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

• Published in: MedChemComm Vol. 9; no. 3; pp. 545 - 553
• Main Authors: Cousin, David, Hummersone, Marc G., Bradshaw, Tracey D., Zhang, Jihong, Moody, Christopher J., Foreiter, Magdalena B., Summers, Helen S., Lewis, William, Wheelhouse, Richard T., Stevens, Malcolm F. G.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.03.2018; Royal Society of Chemistry
• Subjects: Biochemistry & Molecular Biology; Biotechnology; Cell lines; Chemistry; Chemistry, Medicinal; Deoxyribonucleic acid; Derivatives; DNA; DNA methyltransferase; DNA repair; Glioma cells; Life Sciences & Biomedicine; Methylguanine; O6-methylguanine-DNA methyltransferase; Pharmacology & Pharmacy; Science & Technology; Silicon; Substitutes; Temozolomide; Tumors; CHEMISTRY; RESISTANCE; ACTIVATION; CRYSTAL; AGENTS; IMIDAZOTETRAZINES
• DOI: 10.1039/C7MD00554G
• ISSN: 2040-2503

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 O 6 -methylguanine-DNA methyltransferase (MGMT). In general the compounds had low inhibitory activity with GI 50 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.