Date of Award

2026-05-01

Degree Name

Master of Science

Department

Chemistry

Advisor(s)

Amol Kulkarni

Abstract

Glioblastoma multiforme (GBM) is an aggressive brain tumor with rapid progression and poor prognosis. Although temozolomide (TMZ) remains a central component of standard therapy, its clinical benefit is limited and resistance frequently emerges through DNA repair pathways, particularly O6-methylguanine-DNA methyltransferase (MGMT). Because DNA cross-links are generally more difficult to repair than monoalkylated lesions, we hypothesized that TMZ derivatives bearing protein-reactive functionality might generate damage that is less susceptible to MGMT-mediated resistance. Guided by this rationale, we designed a new class of N3-modified TMZ derivatives containing covalent warheads, developed a synthetic route compatible with the chemical instability of the TMZ scaffold, and identified Z68 as a lead compound. Z68 showed substantially improved antiproliferative activity relative to TMZ in TMZ-resistant T98G cells while retaining strong activity in U87 cells. In cell-cycle studies, TMZ produced the expected G2/M arrest in U87 cells, whereas Z68 caused little to no detectable cell-cycle arrest in either U87 or T98G cells, suggesting a mechanism distinct from that of TMZ and classical DNA-DNA cross-linking agents. Quantitative proteomic profiling in U87 cells further indicated that Z68 induces a response pattern different from those of TMZ, MTZ, and KL-50, with selective modulation of nutrient-sensing, mitochondrial-stress, and kinase-associated pathways rather than broad proteome disruption. Together, these findings identify Z68 as a promising TMZ-derived scaffold for overcoming GBM resistance and support a distinct, but still putative, mechanism of action that warrants further biochemical validation. Overall, this study introduces a promising class of TMZ-derived alkylating agents for glioblastoma and establishes a foundation for future validation of their proposed mechanism and therapeutic potential.

Language

en

Provenance

Received from ProQuest

File Size

67 p.

File Format

application/pdf

Rights Holder

Hualin Zhang

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Chemistry Commons

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