Date of Award

2026

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy in Biochemistry and Molecular Biology (PhD)

Administrative Home Department

Department of Chemistry

Advisor 1

Marina Tanasova

Advisor 2

Smitha Rao-Hatti

Committee Member 1

Tarun Dam

Committee Member 2

Mark Tang

Committee Member 3

Robert Larson

Abstract

Metabolic reprogramming toward increased sugar uptake is a hallmark of cancer, and fructose-specific uptake through the facilitative transporter GLUT5 is selectively upregulated in several adenocarcinomas, including breast and lung cancer. This dissertation develops and characterizes a panel of fluorescent fructose mimetics – the coumarin-based ManCou probes and the quinolinone-based ManQuin probes – as GLUT5-targeted reporters, cytotoxic effectors, and chemosensitization adjuvants, and establishes the boundaries within which each role holds.

The central experimental strategy pairs each GLUT5-targeted glycoconjugate with its sugar-free aglycone control, isolating transporter-mediated cytotoxicity from cytotoxicity intrinsic to the fluorophore itself. In luminal (MCF7) and triple-negative (MDA-MB-231) breast carcinoma, the GLUT5-targeted ManCou conjugates produce durable, phenotype-scaled cytotoxicity that exceeds and outlasts that of the matched aglycones, while relatively sparing normal fibroblasts and defining a therapeutic window. The transport-restricting conjugate ManCou-Ph and the quinoline ManQuin-5 additionally sensitize triple-negative lines to the DNA-damaging agents oxaliplatin and cyclophosphamide at sub-cytotoxic concentrations, with the benefit confined to the sub-saturating dose range of each chemotherapeutic.

In A549 lung adenocarcinoma, this relationship inverts: the GLUT5-targeted conjugates are inert across the tested concentration range, while the sugar-free aglycones – particularly the unsubstituted coumarin – produce marked, time-dependent cytotoxicity. This dissociation, further tested using the differently-selective ManQuin probes, identifies a tissue-level boundary on the conjugate-driven mechanism rather than a failure of GLUT5 routing, and reframes A549 cytotoxicity as intrinsic to the fluorophore rather than transporter-mediated.

Across all phenotypes, the ManQuin probes maintain low intrinsic cytotoxicity through 72 hours of continuous exposure and impose no latent or post-washout toxicity, validating their use as non-perturbing reporters of GLUT5 activity independent of their role as effectors elsewhere in the panel.

Together, these results establish a matched aglycone-conjugate framework for isolating GLUT5-mediated effects from off-target fluorophore activity and demonstrate that a single probe scaffold can serve three distinct roles, reporter, effector, and chemosensitization adjuvant, with the operative role determined by cell-line phenotype and by which structural feature of the probe is engaged.

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