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

Abstract

A series of 3-(benzyl-substituted)-imidazo[5,1-<i>d</i>]-1,2,3,5-tetrazines (<b>13</b>) and related derivatives with 3-heteromethyl groups has been synthesised and screened for growth-inhibitory activity <i>in vitro</i> against two pairs of glioma cell lines with temozolomide-sensitive and -resistant phenotypes dependent on the absence/presence of the DNA repair protein <i>O</i>⁶-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 (<b>9</b>) and the SEM-analogue (<b>10</b>), showed interesting differences: compound (<b>9</b>) 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 (<b>10</b>) showed potency across all cell lines irrespective of their MGMT status.