Development of imidazotetrazines for the treatment of glioblastoma & as synthetic precursors to diazo species

Svec, Riley Larson

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https://hdl.handle.net/2142/108250 Copy

Description

Title

Development of imidazotetrazines for the treatment of glioblastoma & as synthetic precursors to diazo species

Author(s)

Svec, Riley Larson

Issue Date

2020-04-16

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J

Doctoral Committee Chair(s)

Hergenrother, Paul J

Committee Member(s)

• Burke, Martin D
• Fan, Timothy M
• Sarlah, David

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Glioblastoma
• Temozolomide
• TMZ
• Imidazotetrazine
• Diazomethane

Abstract

Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most prevalent, aggressive, and deadly form of malignant brain tumor with only 10% of patients surviving five years. The current standard treatment for GBM patients is bulk surgical resection and radiotherapy with concomitant and adjuvant temozolomide (TMZ), a small molecule DNA alkylating agent. The antitumor effect of TMZ is ultimately mediated through methylation of the O6-position of guanine and subsequent mismatch repair (MMR)-dependent cell death. Although TMZ was first synthesized in 1984 and has been FDA approved for two decades, certain key derivatives have been inaccessible due to synthetic challenges, precluding a broad exploration of the link between imidazotetrazine structure and biological activity. Novel synthetic strategies provided access to several new classes of C8-substituted imidazotetrazines and an evaluation of their aqueous stabilities enabled the derivation of a predictive model for imidazotetrazine hydrolytic stability based on the Hammett constant of the C8 substituent. Promising compounds modified at the C8 position were identified and found to have appropriate hydrolytic stability, enhanced blood-brain barrier permeability, lower hematological toxicity profiles, and superior activity relative to TMZ in a mouse model of GBM. Despite its widespread use, certain GBM patient populations do not respond to TMZ therapy. Expression of O6-methylguanine DNA methyltransferase (MGMT) and loss of MMR function are the primary clinical modes of resistance to TMZ. Imidazotetrazine analogs modified at the N3 position were designed to deliver alternative DNA adducts that were irremovable by MGMT. An analog bearing a propargyl group at N3 demonstrated MGMT-independent activity in GBM cells in culture. Tuning the stability with an electron-donating chloro substituent at the C8 position produced novel dual-substituted imidazotetrazine CPZ, which displayed anticancer activity irrespective of MGMT expression and MMR status. Imidazotetrazines such as TMZ are precursors to alkyl diazoniums, used therapeutically to alkylate DNA and elicit an anticancer effect. Given their stability as prodrugs and the reactivity of the species released, imidazotetrazines were repurposed into synthetic surrogates for diazomethane and other diazoalkanes. TMZ was employed to conduct esterifications and metal-catalyzed cyclopropanations, with methyl ester formation from a wide variety of substrates proving efficient and operationally simple. As a commercially available solid that is non-explosive and non-toxic, TMZ should find broad utility as a synthetic replacement for diazomethane.

Graduation Semester

2020-05

Type of Resource

Thesis

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http://hdl.handle.net/2142/108250

Copyright and License Information

Copyright 2020 Riley Svec

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