The current standard-of-care for glioblastoma (GBM) consists of prodrug temozolomide (TMZ), a small molecule DNA alkylating agent. TMZ was first synthesized &gt;30 years ago, but it remains the only approved imidazotetrazine anticancer drug, and no analog has comparatively improved survival in an intracranial model of GBM. TMZ provides a survival benefit of ~2 years to GBM patients whose tumors do not express MGMT. However, a majority of GBM tumors (&gt;55%) express high levels and these patients derive no benefit from the drug. Considering the large discrepancy in treatment effectiveness, imidazotetrazines substituted at the N3-position were designed to deliver an alternative DNA adduct (instead of a methyl group). Several such derivatives demonstrated equivalent activity in both MGMT-expressing and non-expressing cell lines, suggesting that the adducts were not susceptible to removal by MGMT. Moreover, although the mechanism of activation of TMZ has been well-established, there is little information on the relationship between prodrug half-life and anticancer activity. As such, novel synthetic methods were developed that afforded a diverse panel of C8-substituted imidazotetrazines. A direct relationship was revealed between the group at C8 and the aqueous stability of the prodrug, which enabled the rational design of compounds that not only demonstrated appropriate half-lives, but also possessed additional advantageous properties such as increased blood-brain barrier (BBB) penetration. Augmented BBB-permeability was identified in vivo for several compounds, which led to increased efficacy versus TMZ in mouse models of GBM. The dramatic partitioning to the brain also alleviated drug-induced hematological toxicity (dose-limiting for TMZ) in vivo. Finally, the unique activation mechanism of TMZ, releasing methyl diazonium slowly over time in water, suggested that it may have relevance in chemical synthesis as a solid-state surrogate for diazomethane. We further demonstrate the exploration of imidazotetrazines as precursors of diazomethane that can effect in situ, one-pot esterifications and cyclopropanations.

Imidazotetrazines for the treatment of glioblastoma and as synthetic diazoalkane precursors

2019 Fall National Meeting

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