Towards the Synthesis of Temozolomide Theragnostic Derivatives

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Authors
Hart, Lucy
Issue Date
2022-11-01
Type
Thesis
Language
en_US
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Abstract
Glioblastoma multiforme (GBM) is the most common and proliferating primary brain tumor with a median survival of 12-15 months. GBM is characterized as having extreme cell proliferation which diffuses throughout the brain and heterogeneity inter/intratumorally, leading to resistance in treatment and a poor prognosis. The current standard-of-care for GBM patients includes surgical resection, radiotherapy, and a DNA-alkylating chemotherapy agent, temozolomide (TMZ). While the current treatment for GBM is extremely aggressive, recurrence after surgical resection is almost inevitable and over 50% of GBM patients do not respond to TMZ therapy; overexpression of a methyltransferase repair enzyme and/or a deficiency in the mismatch repair pathway are the leading factors for resistance. Therefore, the optimal treatment for GBM is still under question. Here, we aim to further investigate two proposed theragnostic TMZ derivatives with an effort to improve maximal resection and specificity of TMZ accumulation in malignant tissue. The first compound, 6-aminofluorescein diacetate-TMZ was synthesized and assessed via a cell viability assay using glioma cell lines. Its results showed extreme levels of cytotoxicity compared to TMZ, suggesting that this compound expressed an alternative mechanism of action independent from TMZ alone. We synthesized and assessed potential products of degradation of 6-aminofluorescein diacetate-TMZ to better understand the reason for extreme cytotoxic levels that are independent from TMZ. The second compound, 5-ALA-TMZ ester was synthesized via two different mechanisms and assessed via a cell viability assay using glioma cell lines. Its results were similar to TMZ, indicating a similar mechanism of action. This compound showed promising results, creating a potential model for synthesizing a theragnostic compound that circumvents TMZ resistance.
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viii, 30 p.
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Kalamazoo College
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U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder. All rights reserved.
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