Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma

Riley L. Svec, Lucia Furiassi, Christine G. Skibinski, Timothy M. Fan, Gregory J. Riggins, Paul J. Hergenrother

Research output: Contribution to journalArticle

Abstract

Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity. Here, we sought to discern the relationship between the hydrolytic stability and anticancer activity of imidazotetrazines, with the objectives of identifying optimal timing for prodrug activation and developing suitable compounds with enhanced efficacy via increased blood-brain barrier penetrance. This work necessitated the development of new synthetic methods to provide access to previously unexplored functionality (such as aliphatic, ketone, halogen, and aryl groups) at the C8 position of imidazotetrazines. Through synthesis and evaluation of a suite of compounds with a range of aqueous stabilities (from 0.5 to 40 h), we derive a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds were identified that possess activity against a panel of GBM cell lines, appropriate hydrolytic and metabolic stability, and brain-to-serum ratios dramatically elevated relative to TMZ, leading to lower hematological toxicity profiles and superior activity to TMZ in a mouse model of GBM. This work points a clear path forward for the development of novel and effective anticancer imidazotetrazines.

Original languageEnglish (US)
Pages (from-to)3206-3216
Number of pages11
JournalACS chemical biology
Volume13
Issue number11
DOIs
StatePublished - Nov 16 2018

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temozolomide
Glioblastoma
Toxicity
Precision Medicine
Halogens
Penetrance
Alkylating Agents
Prodrugs
Standard of Care
Bioactivity
Ketones
Blood-Brain Barrier
Immunotherapy
Medicine
Tumors
Hydrolysis
Brain

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma. / Svec, Riley L.; Furiassi, Lucia; Skibinski, Christine G.; Fan, Timothy M.; Riggins, Gregory J.; Hergenrother, Paul J.

In: ACS chemical biology, Vol. 13, No. 11, 16.11.2018, p. 3206-3216.

Research output: Contribution to journalArticle

Svec, Riley L. ; Furiassi, Lucia ; Skibinski, Christine G. ; Fan, Timothy M. ; Riggins, Gregory J. ; Hergenrother, Paul J. / Tunable Stability of Imidazotetrazines Leads to a Potent Compound for Glioblastoma. In: ACS chemical biology. 2018 ; Vol. 13, No. 11. pp. 3206-3216.
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